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Sample records for hypophyseal metastasis metastasis

  1. Metastasis

    SciTech Connect

    Weller, R.E.

    1991-10-01

    Distant metastasis of primary neoplasms is the main factor that limits the success of antineoplastic therapy. It can be regarded as an early or late event in the neoplastic process, and varies considerably with tumor type. The metastatic potential of a given tumor greatly influences prognosis. Tumor metastasis is not a single neoplastic event, rather, it involves several major steps: invasion of cells from the primary tumor into tissue, and penetration of blood and lymph vessels; release of tumor cell emboli into the circulation; arrest of the emboli in capillary beds of distant organs; invasion of the wall of the arresting vessel, infiltration into adjacent tissue, and multiplication; and growth of vascularized stroma into the new tumor as proliferating tumor cells invade the distant organ. Lodgement and invasion are complex events that are not fully defined. Arrest and lodgement appears to require a thromboembolic event in which the metastatic embolis (1 cell) contacts vascular endothelium and adheres to the wall with thrombis formation following aggregation of platelets and fibrin to the tumor cell(s). Invasion may involve: formation of collagenases by tumor cells; mechanical disruption; chemotactic factors. Metastatic patterns depend on the route of metastasis, tumor type, and target organ (favored soil). In general, carcinomas metastasize via lymphatics and sarcomas via hematogenous routes. Others, melanoma, mast cell tumors, etc., show mixed patterns. This knowledge is important when one is attempting to prognostically stage a tumor, especially when thoracic radiographs are negative. The question of enlarged regional lymph nodes will be discussed in lecture relative to specific tumor types. 4 refs., 1 tab.

  2. Targeting Breast Cancer Metastasis

    PubMed Central

    Jin, Xin; Mu, Ping

    2015-01-01

    Metastasis is the leading cause of breast cancer-associated deaths. Despite the significant improvement in current therapies in extending patient life, 30–40% of patients may eventually suffer from distant relapse and succumb to the disease. Consequently, a deeper understanding of the metastasis biology is key to developing better treatment strategies and achieving long-lasting therapeutic efficacies against breast cancer. This review covers recent breakthroughs in the discovery of various metastatic traits that contribute to the metastasis cascade of breast cancer, which may provide novel avenues for therapeutic targeting. PMID:26380552

  3. [Biology of cancer metastasis].

    PubMed

    Robert, Jacques

    2013-04-01

    Metastatic dissemination represents the true cause of the malignant character of cancers. Its targeting is much more difficult than that of cell proliferation, because metastasis, like angiogenesis, involves a number of complex interactions between tumour and stroma; the contribution of adhesion and motility pathways is added to that of proliferation and survival pathways. Long distance extension, discontinuous in respect to the primitive tumour, is a major feature of cancer and the main cause of patients' death. Cancer cells use two main dissemination pathways: the lymphatic pathway, leading to the invasion of the lymph nodes draining the organs where the tumour evolves; and the blood pathway, leading to the invasion of distant organs such as liver, brain, bone or lung. Metastasis is inscribed within the properties of the primitive tumour, as shown by the comparative molecular analysis of the primitive tumour and its own metastases: their similarity is always more important than what could be expected from the general activation of "metastasis genes" or the inhibition of "metastasis suppressor genes". Among the signalling pathways involved in metastasis, one can mention the integrin pathway, the transforming growth factor beta (TGFβ) pathway, the chemokine pathway, the dependence receptor pathway and many others. These pathways allow the possibility of therapeutic targeting, thanks to therapeutic antibodies or small molecules inhibiting the kinases involved in these signalling pathways, but not a single properly anti-metastatic drug has yet been proposed: the complexity and the diversity of the processes allowing metastasis emergence, as well as the fact that the activation mechanisms are more often epigenetic than genetic and are generally physiological processes misled by the malignant cell, render especially difficult the therapeutic approach of metastasis.

  4. Tumour progression and metastasis

    PubMed Central

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour’s survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible. PMID:26913068

  5. Tumour progression and metastasis.

    PubMed

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour's survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible.

  6. [Bone metastasis and RANKL].

    PubMed

    Nakashima, Tomoki

    2014-08-01

    The mice with a disruption of Rank or Rankl exhibit normal mammary development during puberty, but their mammary epithelium fails to proliferate and form lobuloalveolar structures during pregnancy, resulting in the death of newborns. Hormone replacement therapy is associated with an increased risk of breast cancer. Importantly, specific deletion of RANK in mammary epithelium cells prevents both the onset and progression of medroxyprogesterone acetate (MPA) -driven mammary cancer and impairs self-renewal of breast cancer stem cells. Furthermore, RANK is highly expressed in several cancer cells. Functionally, it has been shown that RANKL can stimulate the directed migration of mammary epithelial cells as well as prostate cancer and melanoma cells toward a source of RANKL. In an in vivo metastasis model, OPG reduced the tumor burden in bones and ameliorated clinical paralysis, but did not affect the frequency of the spread of metastases into other tissues. These findings show that the RANK/RANKL system is crucial for mammary development, breast tumorigenesis and bone metastasis.

  7. [Pancreas pseudocyst or metastasis?].

    PubMed

    Gyorffy, Hajnalka; Tihanyi, Tibor; Gyökeres, Tibor; Zsirka-Klein, Attila; Kádár, Péter; Kaszás, Ilona; Kovács, Margit

    2005-10-23

    The authors review a case of a 24-year-old male patient hospitalised for repeated acute abdominal symptoms. His medical history included no diseases worth of mentioning. By imaging techniques (abdominal US and CT scan) a cystic lesion, measuring 40 x 35 x 30 mm in diameter was found, and was diagnosed as pseudocyst in the region of the tail of the pancreas. Jejunal feeding was introduced. The lesion did not improve and the second CT scan suggested a suspicion of pancreatic cystadenoma. Three months after first presentation the surgical resection was performed. The tumour, however, was found independent of the pancreas (90 x 80 x 50 mm). Both histologically and immunohistochemically the lesion proved to be the metastasis of a germ cell (yolk-sac) tumour. Following the morphological diagnosis, detailed urological and medical check up was performed. A previously nonpalpable small tumour was found in the left testis which was radically resected. The testicular tumour measuring 9 x 9 x 5 mm in diameter was diagnosed as embryonal carcinoma. Later on the patient underwent chemotherapy. He has been undergoing close oncological followup. Clinically, he is disease free. Authors emphasize the importance of imaging techniques and fine needle aspiration cytology in the case of retroperitoneal masses in young males. The possibility of a metastasis, especially of germ cell origin, should be excluded (not only by physical examination, but by ultrasound of testis also) in case of retroperitoneal cystic tumours even with unusual morphology.

  8. Extraneural Glioblastoma Multiforme Vertebral Metastasis

    PubMed Central

    Goodwin, C. Rory; Liang, Lydia; Abu-Bonsrah, Nancy; Hdeib, Alia; Elder, Benjamin D.; Kosztowski, Thomas; Bettegowda, Chetan; Laterra, John; Burger, Peter; Sciubba, Daniel M.

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor; however, extraneural metastasis is uncommon. Of those that metastasize extraneurally, metastases to the vertebral bodies represent a significant proportion. We present a review of 28 cases from the published literature of GBM metastasis to the vertebra. The mean age at presentation was 38.4 years with an average overall survival of 26 months. Patients were either asymptomatic with metastasis discovered at autopsy or presented with varying degrees of pain, weakness of the extremities, or other neurologic deficits. Of the cases that included the time to spinal metastasis, the average time was 26.4 months with a reported survival of 10 months after diagnosis of vertebral metastasis. A significant number of patients had no treatments for their spinal metastasis, although the intracranial lesions were treated extensively with surgery and/or adjuvant therapy. With increasing incremental gains in the survival of patients with GBM, clinicians will encounter patients with extracranial metastasis. As such, this review presents timely information concerning the presentation and outcomes of patients with vertebral metastasis. PMID:26704201

  9. Extraneural Glioblastoma Multiforme Vertebral Metastasis.

    PubMed

    Goodwin, C Rory; Liang, Lydia; Abu-Bonsrah, Nancy; Hdeib, Alia; Elder, Benjamin D; Kosztowski, Thomas; Bettegowda, Chetan; Laterra, John; Burger, Peter; Sciubba, Daniel M

    2016-05-01

    Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor; however, extraneural metastasis is uncommon. Of those that metastasize extraneurally, metastases to the vertebral bodies represent a significant proportion. We present a review of 28 cases from the published literature of GBM metastasis to the vertebra. The mean age at presentation was 38.4 years with an average overall survival of 26 months. Patients were either asymptomatic with metastasis discovered at autopsy or presented with varying degrees of pain, weakness of the extremities, or other neurologic deficits. Of the cases that included the time to spinal metastasis, the average time was 26.4 months with a reported survival of 10 months after diagnosis of vertebral metastasis. A significant number of patients had no treatments for their spinal metastasis, although the intracranial lesions were treated extensively with surgery and/or adjuvant therapy. With increasing incremental gains in the survival of patients with GBM, clinicians will encounter patients with extracranial metastasis. As such, this review presents timely information concerning the presentation and outcomes of patients with vertebral metastasis. PMID:26704201

  10. Mandible metastasis of hepatocellular carcinoma.

    PubMed

    Niedzielska, Iwona; Langowska-Adamczyk, Helena; Pajak, Jacek; Kajor, Maciej; Niedzielski, Zbigniew; Gołka, Dariusz

    2004-01-01

    Metastases to oral cavity are very uncommon. We present a case of hepatocellular carcinoma (HCC) metastasis to the jaw. The x-ray examination and clinical picture of the lesion were not characteristic. The gingival metastasis may mimic other benign and malignant conditions which affect jaw and therefore the histopathological examination is necessary to make an ultimate diagnosis.

  11. Molecular Mechanisms of Bone Metastasis.

    PubMed

    Weidle, Ulrich H; Birzele, Fabian; Kollmorgen, Gwendlyn; Rüger, Rüdiger

    2016-01-01

    Metastasis of breast and prostate cancer as well as multiple myeloma to the bones represents a significant medical problem. We herein discuss the molecular basis of the creation of pre-metastatic niches, the process of bone metastasis and the phenomenon of tumor dormancy in the bone marrow as well as its regulation. We describe the identification and validation of genes mediating bone metastasis by use of pre-clinical models of bone metastasis. Additionally, we discuss the role of small integrin binding N-linked glycoproteins (SIBLINGS), the chemokine/chemokine receptor CXCL12/CXCR4 pathway and the role of micro RNAs (miRNAs) as mediators of bone metastasis. Finally, we summarize clinical achievements for the treatment of bone metastases.

  12. Imaging of ocular melanoma metastasis.

    PubMed

    Balasubramanya, Rashmi; Selvarajan, Santosh Kumar; Cox, Mougnyan; Joshi, Ganesh; Deshmukh, Sandeep; Mitchell, Donald G; O'Kane, Patrick

    2016-09-01

    Ocular melanoma is the most common adult primary intraocular tumour. Although <1% of patients have metastatic disease at the time of initial diagnosis, most will develop metastasis at varying lengths of time. Metastasis surveillance is therefore critical in the follow-up of patients with ocular melanoma. Liver is the most common site of metastasis and prognosis is based on the treatment of liver metastasis. Hence, imaging of liver metastasis is vital. MRI is the most specific modality for imaging liver metastasis and is at least as sensitive as CT. Extrahepatic metastasis such as retroperitoneal nodules and bone metastases are also better evaluated on MRI. Gadolinium-based contrast agents are extremely helpful for detecting liver lesions. In particular, newer hepatobiliary contrast agents which offer an additional hepatobiliary phase of excretion help in the detection of even tiny liver metastases. Diffusion-weighted imaging is helpful when an i.v. contrast cannot be administered. Treated lesions are also better evaluated with MRI. CT is useful for evaluating lung nodules, large liver metastasis or in patients in whom MRI is medically contraindicated. The disadvantage lies in its inability to detect small liver metastasis and the radiation dose involved. The lesions treated with iodized oil as part of chemoembolization procedures can be followed on CT. Ultrasound can be used only for detecting hepatic metastases. However, it is heavily operator dependent, technically challenging and time consuming especially in patients who are large. Extrahepatic metastasis cannot be seen on ultrasound. Its utility is primarily for the biopsy of liver lesions. Positron emission tomography (PET)-CT can detect lung nodules and large liver lesions but is insensitive to small liver lesions. Moreover, the high radiation dose is a major disadvantage. PMID:27168029

  13. Hypoxic control of metastasis

    PubMed Central

    Rankin, Erinn B.; Giaccia, Amato J.

    2016-01-01

    Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease. PMID:27124451

  14. Gastric adenocarcinoma with prostatic metastasis.

    PubMed

    Roshni, S; Anoop, Tm; Preethi, Tr; Shubanshu, G; Lijeesh, Al

    2014-06-01

    Metastasis of gastric adenocarcinoma to the prostate gland is extremely rare. Herein, we report a case of gastric adenocarcinoma in a 56-year-old man with prostatic metastasis diagnosed through the analysis of biopsy specimens from representative lesions in the stomach and prostate gland. Immunohistochemistry of the prostatic tissue showed positive staining for cytokeratin 7 and negative staining for prostate-specific antigen (PSA), whereas the serum PSA level was normal, confirming the diagnosis of prostatic metastasis from carcinoma of the stomach. PMID:25061542

  15. Gastric Adenocarcinoma with Prostatic Metastasis

    PubMed Central

    Roshni, S; Preethi, TR; Shubanshu, G; Lijeesh, AL

    2014-01-01

    Metastasis of gastric adenocarcinoma to the prostate gland is extremely rare. Herein, we report a case of gastric adenocarcinoma in a 56-year-old man with prostatic metastasis diagnosed through the analysis of biopsy specimens from representative lesions in the stomach and prostate gland. Immunohistochemistry of the prostatic tissue showed positive staining for cytokeratin 7 and negative staining for prostate-specific antigen (PSA), whereas the serum PSA level was normal, confirming the diagnosis of prostatic metastasis from carcinoma of the stomach. PMID:25061542

  16. Bone resorption, metastasis, and diphosphonates

    SciTech Connect

    Garattini, S.

    1985-01-01

    This book contains 17 selections. Some of the titles are: Radiotherapy of Bone Lesions; Methodological Problems; Treatment of Bone Metastasis with Antiresorptive Drugs; Control of Bone Cancer Pain; and Chemotherapy of Bone Metastases.

  17. Modeling metastasis in the mouse

    PubMed Central

    Bos, Paula D.; Nguyen, Don X.; Massagué, Joan

    2010-01-01

    Metastasis is a complex clinical and biological problem presently under intense study, and several model systems are in use to experimentally recapitulate and dissect the various steps of the metastatic process. Genetically engineered mouse models provide faithful renditions of events in tumor progression, angiogenesis, and local invasion that set the stage for metastasis, whereas engrafting of human or mouse tumor tissues into mouse hosts has been successfully exploited to investigate metastatic dissemination and colonization of distant organs. Real-time, high-resolution microscopy in live animals, and comprehensive genetic and molecular profiling are effective tools to interrogate diverse metastatic cancer cell phenotypes as well as the metastatic tumor microenvironment in different organs. By integrating the information obtained with these complementary approaches the field is currently obtaining an unprecedented level of understanding of the biology, molecular basis, and therapeutic vulnerabilities of metastasis. PMID:20598638

  18. [Lymph node metastasis of osteosarcomas].

    PubMed

    Vasil'ev, N V

    2016-01-01

    Lymph node metastasis of osteosarcomas is a rather rare phenomenon; according to different authors, the incidence of lymph node metastasis is 4 to 11%. The detection of lymph node metastases in osteosarcoma is associated with a significant reduction in the 5-year survival of patients and allows its classification as clinical stage IV tumor. The risk factors for lymph node metastases in patients with bone sarcomas are age (≥64 years), gender (female), nosological entity (undifferentiated pleomorphic sarcoma, osteosarcoma, chondrosarcoma), tumor depth (muscle, bone), and the size of primary tumor (>5 сm). The mechanism of lymph node metastasis of osteosarcomas seems to be related to mesenchymal-to-epithelial transition. PMID:27600784

  19. Metastasis genetics, epigenetics, and the tumor microenvironment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    KISS1 is a member of a family of genes known as metastasis suppressors, defined by their ability to block metastasis without blocking primary tumor development and growth. KISS1 re-expression in multiple metastatic cell lines of diverse cellular origin suppresses metastasis; yet, still allows comple...

  20. Intramedullary conus medullaris metastasis of periurethral adenocarcinoma.

    PubMed

    Ramakonar, H H; Thomas, A; Lind, C R P

    2011-04-01

    Intramedullary spinal cord metastasis to the conus medullaris is very rare. We report a 44-year-old woman with an intra-axial conus medullaris metastasis from periurethral adenocarcinoma. To our knowledge, this is the first report in the literature. We also discuss the clinical features, possible pathophysiological mechanisms and treatment options for intramedullary spinal cord metastasis to the conus medullaris.

  1. Vasculogenic mimicry and tumor metastasis.

    PubMed

    Zhang, Jingxin; Qiao, Lili; Liang, Ning; Xie, Jian; Luo, Hui; Deng, Guodong; Zhang, Jiandong

    2016-01-01

    Vasculogenic mimicry (VM), a microvascular channel made up of nonendothelial cells, has been accepted as a new model of neovascularization in aggressive tumors, owning to the specific capacity of malignant cells to form vessel-like networks which provide sufficient blood supply for tumor growth. Multiple molecular mechanisms, especially vascular endothelial (VE)-cadherin, erythropoietin-producing hepatocellular receptor A2 (EphA2), phosphatidyl inositol 3-kinase (PI3K), matrix metalloproteinases (MMPs), vascular endothelial growth factor receptor (VEGFR1), and hypoxia inducible factor (HIF)-1a, have been reported to participate in VM formation which is associated with tumor migration and invasion. In addition, hypoxia, cancer stem cells (CSCs) and epithelial-mesenehymal transition (EMT) are regarded as significant factors in VM formation and tumor metastasis. Due to the important effects of VM on tumor progression, a review was carried out in the present study, to synthetically analyze the relationship between VM and tumor metastasis. PMID:27569069

  2. Animal Models of Bone Metastasis.

    PubMed

    Simmons, J K; Hildreth, B E; Supsavhad, W; Elshafae, S M; Hassan, B B; Dirksen, W P; Toribio, R E; Rosol, T J

    2015-09-01

    Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone.

  3. Animal Models of Bone Metastasis

    PubMed Central

    Simmons, J. K.; Hildreth, B. E.; Supsavhad, W.; Elshafae, S. M.; Hassan, B. B.; Dirksen, W. P.; Toribio, R. E.; Rosol, T. J.

    2015-01-01

    Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. PMID:26021553

  4. Raman spectroscopy of bone metastasis

    NASA Astrophysics Data System (ADS)

    Esmonde-White, Karen A.; Sottnik, Joseph; Morris, Michael; Keller, Evan

    2012-02-01

    Raman spectroscopy of bone has been used to characterize chemical changes occurring in diseases such as osteoporosis, osteoarthritis and osteomyelitis. Metastasis of cancer into bone causes changes to bone quality that are similar to those observed in osteoporosis, such as decreased bone strength, but with an accelerated timeframe. In particular, osteolytic (bone degrading) lesions in bone metastasis have a marked effect on patient quality of life because of increased risk of fractures, pain, and hypercalcemia. We use Raman spectroscopy to examine bone from two different mouse models of osteolytic bone metastasis. Raman spectroscopy measures physicochemical information which cannot be obtained through standard biochemical and histological measurements. This study was reviewed and approved by the University of Michigan University Committee on the Care and Use of Animals. Two mouse models of prostate cancer bone metastasis, RM1 (n=3) and PC3-luc (n=4) were examined. Tibiae were injected with RM1 or PC3-luc cancer cells, while the contralateral tibiae received a placebo injection for use as controls. After 2 weeks of incubation, the mice were sacrificed and the tibiae were examined by Raman microspectroscopy (λ=785 nm). Spectroscopic markers corresponding to mineral stoichiometry, bone mineralization, and mineral crystallinity were compared in spectra from the cancerous and control tibiae. X-ray imaging of the tibia confirmed extensive osteolysis in the RM1 mice, with tumor invasion into adjoining soft tissue and moderate osteolysis in the PC3-luc mice. Raman spectroscopic markers indicate that osteolytic lesions are less mineralized than normal bone tissue, with an altered mineral stoichiometry and crystallinity.

  5. Colorectal hepatic metastasis: Evolving therapies

    PubMed Central

    Macedo, Francisco Igor B; Makarawo, Tafadzwa

    2014-01-01

    The approach for colorectal hepatic metastasis has advanced tremendously over the past decade. Multidrug chemotherapy regimens have been successfully introduced with improved outcomes. Concurrently, adjunct multimodal therapies have improved survival rates, and increased the number of patients eligible for curative liver resection. Herein, we described major advancements of surgical and oncologic management of such lesions, thereby discussing modern chemotherapeutic regimens, adjunct therapies and surgical aspects of liver resection. PMID:25067997

  6. The biology of cancer metastasis.

    PubMed

    Price, J E

    1990-01-01

    The formation of a metastasis entails a complex sequence of events with the end result dependent on the interaction of malignant cells with host factors. Intrinsic properties of the metastatic tumor cells, including production of proteolytic enzymes, cell surface properties, adhesiveness, and the ability to grow in a distant organ environment, act in concert to influence the tumor cells' interactions with host cells in forming metastases. Life-threatening metastases are formed only by those tumor cells that have survived all steps in a process that has been shown in many experimental studies to be a highly selective event. The results of studies on the distribution of radiolabelled mouse melanoma cells injected into syngeneic mice support the concept that the fate of tumor cells released into the bloodstream is determined by sequential and selective events, and introduces a third regulatory factor. Cells endowed with metastatic properties, isolated by cloning a heterogeneous tumor or selected from a metastasis, have a higher probability of forming metastases than cells not so endowed, yet this probability is not 100%. Metastasis should thus be considered as a selective, sequential and stochastic process. Interruption of the process at any stage will prevent the formation of metastatic disease. Hence, a better understanding of the metastatic process will provide the basis for rational approaches for the prevention or destruction of this most fatal aspect of cancer.

  7. Cancer stem cells and metastasis.

    PubMed

    Sampieri, Katia; Fodde, Riccardo

    2012-06-01

    Cancer stem cells (CSCs) represent a subpopulation of tumour cells endowed with self-renewal and multi-lineage differentiation capacity but also with an innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in cancer patients. Operationally, CSCs are defined by their tumour-propagating ability when serially transplanted into immune-compromised mice and by their capacity to fully recapitulate the original heterogeneity of cell types observed in the primary lesions they are derived from. CSCs were first identified in haematopoietic malignancies and later in a broad spectrum of solid tumours including those of the breast, colon and brain. Notably, several CSC characteristics are relevant to metastasis, such as motility, invasiveness and, as mentioned above, resistance to DNA damage-induced apoptosis. Here, we have reviewed the current literature on the relation between CSCs and metastasis formation. Preliminary studies on cancer cell lines and patient-derived material suggest a rate-limiting role for stem-like cells in the processes of tumour cell dissemination and metastasis formation. However, additional studies are needed to deliver formal proof of their identity as the cell of origin of recurrences at distant organ sites. Nevertheless, several studies have already provided pre-clinical evidence of the efficacy of novel therapies directed against disseminated CSCs.

  8. A Case of Pleuroparenchymal Metastasis: Rare Aetiology

    PubMed Central

    Sharma, Radhika; Narasimhan, Meenakshi; Shanmuganathan, Aruna; Rajendran, Adhithyan

    2016-01-01

    A phyllodes tumour is a malignancy of both mesenchymal and epithelial origin affecting the breast. The malignant course of this breast tumour causing lung metastasis is rare. Here we report a treated case of borderline phyllodes tumour that presented with pleuroparenchymal metastasis. Our case highlights the possibility of recurrence of borderline phyllodes tumour as pleuroparenchymal metastasis even after a long disease free interval. PMID:27190865

  9. Endocannabinoids as Guardians of Metastasis

    PubMed Central

    Tegeder, Irmgard

    2016-01-01

    Endocannabinoids including anandamide and 2-arachidonoylglycerol are involved in cancer pathophysiology in several ways, including tumor growth and progression, peritumoral inflammation, nausea and cancer pain. Recently we showed that the endocannabinoid profiles are deranged during cancer to an extent that this manifests in alterations of plasma endocannabinoids in cancer patients, which was mimicked by similar changes in rodent models of local and metastatic cancer. The present topical review summarizes the complexity of endocannabinoid signaling in the context of tumor growth and metastasis. PMID:26875980

  10. A review of penile metastasis

    PubMed Central

    Mearini, Luigi; Colella, Renato; Zucchi, Alessandro; Nunzi, Elisabetta; Porrozzi, Carlo; Porena, Massimo

    2012-01-01

    Penile cancer as primary disease is relatively rare in developed countries. The penis is a rare site of metastases in spite of its rich vascularization. Approximately 500 cases have been reported in the literature; almost 70% of primary lesions are of pelvic origin (from genitourinary or recto-sigmoid primary tumors). We describe a case of penile metastasis from lung cancer. The rarity of the event prompted us to also explore related reviews and discuss the incidence, physiopathology, diagnosis and therapy of penile secondary cancer. PMID:25992200

  11. Metastasis

    MedlinePlus

    ... Trials Pain Management Nutrition and Exercise Holistic Care Pathology Intraductal Papillary Mucinous Neoplasms Islet Cell Tumors & Endocrine ... 410-933-7262 Site Map Policies & Credits News Pathology Home Goldman Center © 2016 Johns Hopkins University

  12. Breast metastasis from vaginal cancer.

    PubMed

    Chandrasekaran, Neeraja; Scharifker, Daniel; Varsegi, George; Almeida, Zoyla

    2016-07-21

    Vaginal cancer is a rare malignancy accounting for 1-2% of all pelvic neoplasms. Dissemination usually occurs through local invasion and rarely metastasises to distal locations. Metastasis of vaginal cancer to the breast is extremely infrequent and unique. A 66-year-old Asian woman presented with vaginal bleeding and was found to have a vaginal mass and a left breast mass. Pathological assessment of the biopsies revealed identical squamous cell characteristics of both masses. We describe a very rare and novel case of a distally located vaginal carcinoma with metastasis to the breast Federation of Gynecology and Obstetrics (FIGO) stage IV (FIGO IVB). Robot-assisted extrafascial total hysterectomy with local vaginal mass excision and partial mastectomy of the left breast were performed. After surgery, the patient underwent adjuvant chemotherapy followed by breast and pelvic radiotherapy, with maintained complete remission after 3 years of follow-up. This combination of findings and treatment is very distinct with a unique and favourable response.

  13. Breast metastasis from vaginal cancer.

    PubMed

    Chandrasekaran, Neeraja; Scharifker, Daniel; Varsegi, George; Almeida, Zoyla

    2016-01-01

    Vaginal cancer is a rare malignancy accounting for 1-2% of all pelvic neoplasms. Dissemination usually occurs through local invasion and rarely metastasises to distal locations. Metastasis of vaginal cancer to the breast is extremely infrequent and unique. A 66-year-old Asian woman presented with vaginal bleeding and was found to have a vaginal mass and a left breast mass. Pathological assessment of the biopsies revealed identical squamous cell characteristics of both masses. We describe a very rare and novel case of a distally located vaginal carcinoma with metastasis to the breast Federation of Gynecology and Obstetrics (FIGO) stage IV (FIGO IVB). Robot-assisted extrafascial total hysterectomy with local vaginal mass excision and partial mastectomy of the left breast were performed. After surgery, the patient underwent adjuvant chemotherapy followed by breast and pelvic radiotherapy, with maintained complete remission after 3 years of follow-up. This combination of findings and treatment is very distinct with a unique and favourable response. PMID:27444140

  14. MicroRNA and Metastasis.

    PubMed

    Ma, L

    2016-01-01

    Noncoding RNAs are important regulatory molecules of cellular processes. MicroRNAs (miRNAs) are small noncoding RNAs that bind to complementary sequences in the 3' untranslated region of target mRNAs, leading to degradation of the target mRNAs and/or inhibition of their translation. Some miRNAs are essential for normal animal development; however, many other miRNAs are dispensable for development but play a critical role in pathological conditions, including tumorigenesis and metastasis. miRNA genes often reside at fragile chromosome sites and are deregulated in cancer. Some miRNAs function as oncogenes or tumor suppressors, collectively termed "oncomirs." Specific metastasis-regulating miRNAs, collectively termed "metastamirs," govern molecular processes and pathways in malignant progression in either a tumor cell-autonomous or a cell-nonautonomous manner. Recently, exosome-transferred miRNAs have emerged as mediators of the tumor-stroma cross talk. In this chapter, we focus on the functions, mechanisms of action, and therapeutic potential of miRNAs, particularly oncomirs and metastamirs. PMID:27613133

  15. Supratentorial metastasis of medulloblastoma in adults

    PubMed Central

    Kumar, Sushil; Handa, Amit; Jha, Deepak K.; Choudhary, Ajay

    2016-01-01

    Two adults, 31 and 20 years of age, developed supratentorial metastasis 3½ years and 11 months, respectively, after gross total removal of their posterior fossa medulloblastoma. The first case developed spinal metastasis as well. Both had undergone craniospinal irradiation. Case 1 underwent laminectomy and case 2 underwent craniotomy because their presenting symptoms required so. PMID:27366282

  16. The vasculature: a vessel for bone metastasis

    PubMed Central

    Raymaekers, Koen; Stegen, Steve; van Gastel, Nick; Carmeliet, Geert

    2015-01-01

    Emerging evidence indicates that the interactions between tumor cells and the bone microenvironment have a crucial role in the pathogenesis of bone metastasis and that they can influence tumor cell dissemination, quiescence and tumor growth in the bone. The vasculature is known to be critical for primary tumor growth, and anti-angiogenesis drugs are approved for the treatment of certain tumor types. The role of the vasculature in bone metastasis is less well known, but recent evidence shows that blood vessels in the bone are a key component of the local microenvironment for the tumor cells and contribute to the different consecutive phases of bone metastasis. A better insight in the importance of the vasculature for bone metastasis may help develop novel treatment modalities that either slow down tumor growth or, preferably, prevent or cure bone metastasis. PMID:27217954

  17. Isolated pancreatic metastasis from melanoma. Case report.

    PubMed

    Portale, T R; Di Benedetto, V; Mosca, F; Trovato, M A; Scuderi, M G; Puleo, S

    2011-03-01

    Pancreas is frequently site of isolated metastasis, approximately in the 40% of cases in patient with previous history of malignant neoplasia, more frequently from renal cell carcinoma. The melanoma metastasis can also interest the pancreas in case of disseminated disease (50% of the cases); more rarely the pancreas is site of isolated metastases from melanoma. The treatment of the pancreatic metastases from melanoma is controversial: the therapeutic choices are few and the role of surgery is not well defined. If the metastasis are confined to the pancreas, the surgical treatment can be useful for better long time survival. We report a rare case of melanoma with pancreatic isolated metastasi in a patient with a previous melanotic metastasis to the inguinal lymph nodes without evidence of primitive tumor.

  18. Orthopaedic perspective on bone metastasis

    PubMed Central

    Molloy, Alan P; O’Toole, Gary C

    2013-01-01

    The incidence of cancer is increasing worldwide, with the advent of a myriad of new treatment options, so is the overall survival of these patients. However, from an orthopaedic perspective, there comes the challenge of treating more patients with a variety of metastatic bone lesions. The consequences of such lesions can be significant to the patient, from pain and abnormal blood results, including hypercalcemia, to pathological fracture. Given the multiple options available, the treatment of bone metastasis should be based on a patient-by patient manner, as is the case with primary bone lesions. It is imperative, given the various lesion types and locations, treatment of bone metastasis should be performed in an individualised manner. We should consider the nature of the lesion, the effect of treatment on the patient and the overall outcome of our decisions. The dissemination of primary lesions to distant sites is a complex pathway involving numerous cytokines within the tumour itself and the surrounding microenvironment. To date, it is not fully understood and we still base a large section of our knowledge on Pagets historic “seed and soil” theory. As we gain further understanding of this pathway it will allow us develop more medical based treatments. The treatment of primary cancers has long been provided in a multi-disciplinary setting to achieve the best patient outcomes. This should also be true for the treatment of bone metastases. Orthopaedic surgeons should be involved in the multidisciplinary treatment of such patients given that there are a variety of both surgical fixation methods and non-operative methods at our disposal. PMID:23878778

  19. Imaging of bone metastasis: An update.

    PubMed

    O'Sullivan, Gerard J; Carty, Fiona L; Cronin, Carmel G

    2015-08-28

    Early detection of skeletal metastasis is critical for accurate staging and optimal treatment. This paper briefly reviews our current understanding of the biological mechanisms through which tumours metastasise to bone and describes the available imaging methods to diagnose bone metastasis and monitor response to treatment. Among the various imaging modalities currently available for imaging skeletal metastasis, hybrid techniques which fuse morphological and functional data are the most sensitive and specific, and positron emission tomography (PET)/computed tomography and PET/magnetic resonance imaging will almost certainly continue to evolve and become increasingly important in this regard.

  20. Isolated Malignant Melanoma Metastasis to the Pancreas

    PubMed Central

    Krag, Christen; Geertsen, Poul; Jakobsen, Linda P.

    2013-01-01

    Summary: Malignant melanomas rarely develop isolated pancreatic metastases. We describe a unique patient who is still alive 22 years following an isolated pancreatic melanoma metastasis, and we review the sparse literature in the field. PMID:25289269

  1. Biology of cancer invasion and metastasis.

    PubMed

    Mareel, M M; Crombez, R

    1992-01-01

    Current concepts of invasion eventually leading to metastasis are discussed and exemplified by cancers of the head and neck mucosa. Invasion occurs at a number of steps, each step making an ecosystem comprising not only the neoplastic cells but also their normal counterparts, a variety of host cells and the extracellular matrix. The ecosystem concept may explain aspects of metastasis such as site-dependence and organ-specificity of cancer metastasis as well as invasiveness of normal leucocytes. Genes implicated in invasion and metastasis are actively searched for. Recently, the epithelial cell-cell adhesion molecule E-cadherin has been identified as an i- (invasion suppressor) gene product, i.e. a molecule the expression of which counterbalances i+ (invasion promotor) gene activity. Downregulation of E-cadherin in human head and neck cancers may account for their invasive and metastatic behaviour.

  2. Accessory spleen hypertrophy mimicking colon cancer metastasis.

    PubMed

    Ates, I; Yazici, O; Yazilitas, D; Ozdemir, N; Zengin, N

    2016-09-01

    Accessory spleen is a congenital form of an ectopic splenic tissue. In this report, we present a case of a patient who was followed with the diagnosis of rectal and sigmoid colon cancer and an accessory spleen hypertrophy, which was thought to be colon cancer metastasis in the left hypochondriac region. After colectomy and splenectomy, accessory spleen that mimics cancer metastasis was diffrentially diagnosed using scintigraphy. PMID:27685531

  3. Parotid gland metastasis originating from malignant meningioma.

    PubMed

    Dmytriw, Adam A; Gullane, Patrick; Bartlett, Eric; Perez-Ordonez, Bayardo; Yu, Eugene

    2013-01-01

    A case of malignant meningioma with metastasis to the parotid gland is reported. A 60-year-old woman with right-sided neurological symptoms secondary to malignant meningioma developed bilateral parotid masses with identical histology to the primary lesion. The primary lesion was differentiated from a benign oligodendroma with MRI, and the radiological features of this extraordinarily rare metastasis are chronicled with MRI and computed tomography.

  4. Ion Channels in Brain Metastasis

    PubMed Central

    Klumpp, Lukas; Sezgin, Efe C.; Eckert, Franziska; Huber, Stephan M.

    2016-01-01

    Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial–mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood–brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation. PMID:27618016

  5. Ion Channels in Brain Metastasis.

    PubMed

    Klumpp, Lukas; Sezgin, Efe C; Eckert, Franziska; Huber, Stephan M

    2016-01-01

    Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial-mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood-brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation. PMID:27618016

  6. Cancer invasion and metastasis: changing views.

    PubMed

    Duffy, M J; McGowan, P M; Gallagher, W M

    2008-02-01

    The formation of distant metastasis is the main cause of morbidity and mortality in patients with cancer. The aim of this article is to review recent advances in molecular and clinical aspects of metastasis. Traditionally, genes encoding extracellular matrix (ECM) processing proteases, adhesion proteins, and motility factors were thought to be amongst the main mediators of metastasis. Recently, however, genes activated during the early stages of tumourigenesis were implicated in the process. Conversely, genes thought to be primarily involved in metastasis such as urokinase plasminogen (uPA) and certain matrix metalloproteases (MMPs) are now known to also play a role in the early steps of tumour progression, perhaps by stimulating cell proliferation and/or promoting angiogenesis. Paradoxically, certain endogenous protease inhibitors such as PAI-1 and TIMP-1 appear to promote cancer metastasis rather than inhibiting the process. These recent advances in our understanding should lead to the development of new molecular markers for predicting the likely formation of metastasis as well as the identification of new targets for anti-metastatic therapies.

  7. Detection of cancer before distant metastasis

    PubMed Central

    2013-01-01

    Background To establish a distant metastasis (DM) cells must disseminate from the primary tumor and overcome a series of obstacles, the metastatic cascade. In this study we develop a mathematical model for this cascade to estimate the tumor size and the circulating tumor cell (CTC) load before the first metastasis has formed from a primary breast cancer tumor. Methods The metastatic cascade is described in discrete steps: 1. local tumor growth; 2. dissemination into circulation; 3. survival in circulation; 4. extravasation into tissue; and 5. growth into a metastasis. The model was built using data and relationships described in the literature to predict the relationship between tumor size and probability of distant metastasis for 38715 patients with surgically removed TXNXM0 primary breast cancer from the Netherlands Cancer Registry. The model was calibrated using primary tumor size, probability of distant metastasis and time to distant metastasis for 1489 patients with stage T1BNXM0 (25% of total patients with T1BNXM0). Validation of the model was done with data for all patients. Results From the time to distant metastasis of these 38715 breast cancer patients, we determined a tumor doubling time of 1.7 ± 0.9 months. Fitting the data for 25% of T1B patients estimates a metastatic efficiency of 1 metastasis formed per 60 million disseminated tumor cells. Validation of the model to data of patients in all T-stages shows good agreement between model and epidemiological data. To reduce the 5-year risk of distant metastasis for TXNXM0 from 9.2% to 1.0%, the primary tumor needs to be detected and removed before it reaches a diameter of 2.7 ± 1.6 mm. At this size, the model predicts that there will be 9 ± 6 CTC/L blood. Conclusions To reduce the rate of distant metastasis in surgically treated TXNXM0 breast cancer to 1%, imaging technology will need to be able to detect lesions of 2.7 mm in diameter or smaller. Before CTC detection can be applied in

  8. Invasive cancer cells and metastasis

    NASA Astrophysics Data System (ADS)

    Mierke, Claudia Tanja

    2013-12-01

    The physics of cancer is a relatively new emerging field of cancer research. In the last decade it has become a focus of biophysical research as well as becoming a novel focus for classical cancer research. This special section of Physical Biology focusing on invasive cancer cells and metastasis (physical oncology) will give greater insight into the different subfields where physical approaches are being applied to cancer research. This focus on the physical aspects of cancer is necessary because novel approaches in the field of genomics and proteomics have not altered the field of cancer research dramatically, due to the fact that few breakthroughs have been made. It is still not understood why some primary tumors metastasize and thus have a worse outcome compared to others that do not metastasize. As biophysicists, we and others suggest that the mechanical properties of the cancer cells, which possess the ability to transmigrate, are quite different compared to non-metastatic and non-invasive cancer cells. Furthermore, we hypothesize that these cancer cells undergo a selection process within the primary tumor that enables them to weaken their cell-cell adhesions and to alter their cell-matrix adhesions in order to be able to cross the outermost boundary of the primary tumor, as well as the surrounding basement membrane, and to invade the connective tissue. This prerequisite may also help the cancer cells to enter blood or lymph vessels, get transported with the vessel flow and form secondary tumors either within the vessel, directly on the endothelium, or in a different organ after crossing the endothelial lining a second time. This special section begins with a paper by Mark F Coughlin and Jeffrey J Fredberg on the changes in cytoskeletal dynamics and nonlinear rheology due to the metastatic capability of cancer cells from different cancer tissue types such as skin, bladder, prostate and kidney [1]. The hypothesis was that the metastatic outcome is impacted by

  9. An evidence-based knowledgebase of metastasis suppressors to identify key pathways relevant to cancer metastasis

    PubMed Central

    Zhao, Min; Li, Zhe; Qu, Hong

    2015-01-01

    Metastasis suppressor genes (MS genes) are genes that play important roles in inhibiting the process of cancer metastasis without preventing growth of the primary tumor. Identification of these genes and understanding their functions are critical for investigation of cancer metastasis. Recent studies on cancer metastasis have identified many new susceptibility MS genes. However, the comprehensive illustration of diverse cellular processes regulated by metastasis suppressors during the metastasis cascade is lacking. Thus, the relationship between MS genes and cancer risk is still unclear. To unveil the cellular complexity of MS genes, we have constructed MSGene (http://MSGene.bioinfo-minzhao.org/), the first literature-based gene resource for exploring human MS genes. In total, we manually curated 194 experimentally verified MS genes and mapped to 1448 homologous genes from 17 model species. Follow-up functional analyses associated 194 human MS genes with epithelium/tissue morphogenesis and epithelia cell proliferation. In addition, pathway analysis highlights the prominent role of MS genes in activation of platelets and coagulation system in tumor metastatic cascade. Moreover, global mutation pattern of MS genes across multiple cancers may reveal common cancer metastasis mechanisms. All these results illustrate the importance of MSGene to our understanding on cell development and cancer metastasis. PMID:26486520

  10. First description of cervical intradural thymoma metastasis

    PubMed Central

    Marotta, Nicola; Mancarella, Cristina; Colistra, Davide; Landi, Alessandro; Dugoni, Demo Eugenio; Delfini, Roberto

    2015-01-01

    Thymoma and thymic carcinoma are rare epithelial tumors, which originate from the thymus gland. According to the World Health Organization there are “organotypic” (types A, AB, B1, B2, and B3) and “non-organotypic” (thymic carcinomas) thymomas. Type B3 thymomas are aggressive tumors, which can metastasize. Due to the rarity of these lesions, only 7 cases of extradural metastasis are described in the literature. We report the first and unique case of a man with cervical intradural B3 thymoma metastasis. A 46-year-old man underwent thymoma surgical removal. The year after the procedure he was treated for a parietal pleura metastasis. In 2006 he underwent cervical-dorsal extradural metastasis removal and C5-Th1 stabilization. Seven years after he came to our observation complaining left cervicobrachialgia and a reduction of strength of the left arm. He underwent a cervical spine magnetic resonance imaging, which showed a new lesion at the C5-C7 level. The patient underwent a surgery for the intradural B3 thymoma metastasis. Neurological symptoms improved although the removal was subtotal. He went through postoperative radiation therapy with further mass reduction. Spinal metastases are extremely rare. To date, only 7 cases of spinal extradural metastasis have been described in the literature. This is the first case of spinal intradural metastasis. Early individuation of these tumors and surgical treatment improve neurological outcome in patients with spinal cord compression. A multimodal treatment including neoadjuvant chemotherapy, surgery and postoperative radiation therapy seems to improve survival in patients with metastatic thymoma. PMID:26601098

  11. First description of cervical intradural thymoma metastasis.

    PubMed

    Marotta, Nicola; Mancarella, Cristina; Colistra, Davide; Landi, Alessandro; Dugoni, Demo Eugenio; Delfini, Roberto

    2015-11-16

    Thymoma and thymic carcinoma are rare epithelial tumors, which originate from the thymus gland. According to the World Health Organization there are "organotypic" (types A, AB, B1, B2, and B3) and "non-organotypic" (thymic carcinomas) thymomas. Type B3 thymomas are aggressive tumors, which can metastasize. Due to the rarity of these lesions, only 7 cases of extradural metastasis are described in the literature. We report the first and unique case of a man with cervical intradural B3 thymoma metastasis. A 46-year-old man underwent thymoma surgical removal. The year after the procedure he was treated for a parietal pleura metastasis. In 2006 he underwent cervical-dorsal extradural metastasis removal and C5-Th1 stabilization. Seven years after he came to our observation complaining left cervicobrachialgia and a reduction of strength of the left arm. He underwent a cervical spine magnetic resonance imaging, which showed a new lesion at the C5-C7 level. The patient underwent a surgery for the intradural B3 thymoma metastasis. Neurological symptoms improved although the removal was subtotal. He went through postoperative radiation therapy with further mass reduction. Spinal metastases are extremely rare. To date, only 7 cases of spinal extradural metastasis have been described in the literature. This is the first case of spinal intradural metastasis. Early individuation of these tumors and surgical treatment improve neurological outcome in patients with spinal cord compression. A multimodal treatment including neoadjuvant chemotherapy, surgery and postoperative radiation therapy seems to improve survival in patients with metastatic thymoma. PMID:26601098

  12. First description of cervical intradural thymoma metastasis.

    PubMed

    Marotta, Nicola; Mancarella, Cristina; Colistra, Davide; Landi, Alessandro; Dugoni, Demo Eugenio; Delfini, Roberto

    2015-11-16

    Thymoma and thymic carcinoma are rare epithelial tumors, which originate from the thymus gland. According to the World Health Organization there are "organotypic" (types A, AB, B1, B2, and B3) and "non-organotypic" (thymic carcinomas) thymomas. Type B3 thymomas are aggressive tumors, which can metastasize. Due to the rarity of these lesions, only 7 cases of extradural metastasis are described in the literature. We report the first and unique case of a man with cervical intradural B3 thymoma metastasis. A 46-year-old man underwent thymoma surgical removal. The year after the procedure he was treated for a parietal pleura metastasis. In 2006 he underwent cervical-dorsal extradural metastasis removal and C5-Th1 stabilization. Seven years after he came to our observation complaining left cervicobrachialgia and a reduction of strength of the left arm. He underwent a cervical spine magnetic resonance imaging, which showed a new lesion at the C5-C7 level. The patient underwent a surgery for the intradural B3 thymoma metastasis. Neurological symptoms improved although the removal was subtotal. He went through postoperative radiation therapy with further mass reduction. Spinal metastases are extremely rare. To date, only 7 cases of spinal extradural metastasis have been described in the literature. This is the first case of spinal intradural metastasis. Early individuation of these tumors and surgical treatment improve neurological outcome in patients with spinal cord compression. A multimodal treatment including neoadjuvant chemotherapy, surgery and postoperative radiation therapy seems to improve survival in patients with metastatic thymoma.

  13. On the Origin of Cancer Metastasis

    PubMed Central

    Seyfried, Thomas N.; Huysentruyt, Leanne C.

    2013-01-01

    Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs. Currently, several hypotheses have been advanced to explain the origin of cancer metastasis. These involve an epithelial mesenchymal transition, an accumulation of mutations in stem cells, a macrophage facilitation process, and a macrophage origin involving either transformation or fusion hybridization with neoplastic cells. Many of the properties of metastatic cancer cells are also seen in normal macrophages. A macrophage origin of metastasis can also explain the long-standing “seed and soil” hypothesis and the absence of metastasis in plant cancers. The view of metastasis as a macrophage metabolic disease can provide novel insight for therapeutic management. PMID:23237552

  14. Tumour exosome integrins determine organotropic metastasis.

    PubMed

    Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Tesic Mark, Milica; Molina, Henrik; Kohsaka, Shinji; Di Giannatale, Angela; Ceder, Sophia; Singh, Swarnima; Williams, Caitlin; Soplop, Nadine; Uryu, Kunihiro; Pharmer, Lindsay; King, Tari; Bojmar, Linda; Davies, Alexander E; Ararso, Yonathan; Zhang, Tuo; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M; Dumont-Cole, Vanessa D; Kramer, Kimberly; Wexler, Leonard H; Narendran, Aru; Schwartz, Gary K; Healey, John H; Sandstrom, Per; Labori, Knut Jørgen; Kure, Elin H; Grandgenett, Paul M; Hollingsworth, Michael A; de Sousa, Maria; Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K; Jarnagin, William R; Brady, Mary S; Fodstad, Oystein; Muller, Volkmar; Pantel, Klaus; Minn, Andy J; Bissell, Mina J; Garcia, Benjamin A; Kang, Yibin; Rajasekhar, Vinagolu K; Ghajar, Cyrus M; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Lyden, David

    2015-11-19

    Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

  15. Tumour exosome integrins determine organotropic metastasis

    PubMed Central

    Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Mark, Milica Tesic; Molina, Henrik; Kohsaka, Shinji; Di Giannatale, Angela; Ceder, Sophia; Singh, Swarnima; Williams, Caitlin; Soplop, Nadine; Uryu, Kunihiro; Pharmer, Lindsay; King, Tari; Bojmar, Linda; Davies, Alexander E.; Ararso, Yonathan; Zhang, Tuo; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M.; Dumont-Cole, Vanessa D.; Kramer, Kimberly; Wexler, Leonard H.; Narendran, Aru; Schwartz, Gary K.; Healey, John H.; Sandstrom, Per; Labori, Knut Jørgen; Kure, Elin H.; Grandgenett, Paul M.; Hollingsworth, Michael A.; de Sousa, Maria; Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K.; Jarnagin, William R.; Brady, Mary S.; Fodstad, Oystein; Muller, Volkmar; Pantel, Klaus; Minn, Andy J.; Bissell, Mina J.; Garcia, Benjamin A.; Kang, Yibin; Rajasekhar, Vinagolu K.; Ghajar, Cyrus M.; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Lyden, David

    2015-01-01

    Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis. PMID:26524530

  16. The protein C pathway in cancer metastasis.

    PubMed

    Spek, C Arnold; Arruda, Valder R

    2012-04-01

    Cancer is frequently associated with activation of blood coagulation, which in turn has been suggested to promote tumor growth and metastasis. Indeed, low molecular weight heparin treatment significantly prolongs the survival of a wide variety of patients with cancer. Based on this notion that anticoagulant treatment seems to benefit cancer patients, recent experiments aimed to elucidate the importance of the natural anticoagulant protein C pathways in cancer progression. Interestingly, these experiments showed that the repeated administration of exogenous activated protein C limits cancer cell extravasation in experimental animal models. In line, reducing endogenous activated protein C activity dramatically increased the number of experimental metastasis. These data thus strongly suggest that exogenous activated protein C administration may be a novel therapeutic avenue to limit cancer metastasis thereby prolonging overall survival of cancer patients. The current review provides an overview of recent data on the role of the protein C pathway in cancer metastasis. It discusses the potential of activated protein C as a novel target to reduce cancer progression, it points to several limitations of activated protein C administration in the setting of cancer cell metastasis and it suggest zymogen protein C as an attractive alternative. PMID:22682140

  17. Intraorbital metastasis from solitary fibrous tumor.

    PubMed

    Patel, Mrinali M; Jakobiec, Frederick A; Zakka, Fouad R; Du, Rose; Annino, Donald J; Borboli-Gerogiannis, Sheila; Daniels, Anthony B

    2013-01-01

    Solitary fibrous tumor (SFT) is a rare spindle cell tumor of mesenchymal origin that usually arises from pleura or pericardium but can also arise from many extraserosal sites. Although more than 50 cases of primary SFT of the orbit have been reported, there are no reports to date of a malignant nonophthalmic SFT metastasizing in the orbital soft tissues (although sphenoid wing bony involvement has been reported). The authors report here the first case of a patient with intraorbital metastasis of a CD34-positive malignant SFT. The patient was a 57-year-old man with a history of malignant pleural SFT and a prior kidney metastasis. He presented with the rapid appearance of proptosis and massive conjunctival chemosis preventing eyelid closure, and he was found to have a well-circumscribed metastasis to his lateral rectus muscle. Surgical excision cured his ocular symptoms, although he died 3 months later from brain and widespread metastases.

  18. Solitary metachronous splenic metastasis from cutaneous melanoma

    PubMed Central

    Gavriilidis, Paschalis; Goupou, Eleni

    2012-01-01

    Melanoma has been found to metastasise to the spleen, usually in cases of disseminated disease. Solitary splenic metastasis from cutaneous melanoma is very rare. Herein we report the case of a 43-year-old man who developed solitary splenic metastasis from cutaneous melanoma. The patient was operated for T4b N1a Mo superficial spreading melanoma of the anterior thoracic wall. He subsequently underwent left axillary lymph node dissection due to a positive sentinel lymph node. The 33 retrieved lymph nodes were negative for metastasis. The patient received adjuvant therapy with high-dose interferon α-2b. After 27 months and during the follow-up visit an increasing lactate dehydrogenase serum level was observed. Furthermore, CT of the whole body revealed a solitary hypodense tumour of the spleen 9 cm×6 cm. Curative splenectomy was performed and the histopathological report confirmed metastatic melanoma to the spleen. PMID:23104633

  19. Micromanaging of tumor metastasis by extracellular vesicles.

    PubMed

    Tominaga, Naoomi; Katsuda, Takeshi; Ochiya, Takahiro

    2015-04-01

    Extracellular vesicles (EVs) are nanometer-sized membranous vesicles that are released by a variety of cell types into the extracellular space. In the past two decades, EVs have emerged as novel mediators of cancer biology. Many reports have demonstrated the contribution of EVs to cancer metastasis. Metastasis is a multistep process that is responsible for the majority of deaths in cancer patients. This process includes proliferation, angiogenesis, immune modulation, extravasation, intravasation, and colonization. EVs from cancer cells impact these steps through modulation of the host immune system, angiogenesis, and pre-/pro-metastatic niche formation. In this review, we summarize the function of EVs in cancer metastasis. In addition, we also discuss the hurdles to be overcome for further developing this research field. PMID:25746922

  20. Hematogenous Gastric Metastasis of Pancreatic Cancer

    PubMed Central

    Sasajima, Junpei; Okamoto, Kotaro; Taniguchi, Masato

    2016-01-01

    While the gastric involvement of pancreatic cancer is occasionally observed as the result of direct invasion, hematogenous gastric metastasis is rare. A 72-year-old Japanese male presented with general fatigue, pollakiuria, and thirst. Computed tomography revealed a 4.6-cm solid mass in the pancreatic tail and a 4.2-cm multilocular cystic mass in the pancreatic head with multiple liver and lymphatic metastasis. Notably, two solid masses were detected in the gastric wall of the upper body and the antrum; both were separated from the primary pancreatic cancer and seemed to be located in the submucosal layer. Esophagogastroduodenoscopy revealed a submucosal tumor with a normal mucosa in the posterior wall of the upper body of the stomach, suggesting the gastric hematogenous metastasis of pancreatic cancer. The suspected diagnosis was unresectable pancreatic cancer with multiple metastases that was concomitant with the intraductal papillary mucinous neoplasm of the pancreas. PMID:27403106

  1. Hematogenous Gastric Metastasis of Pancreatic Cancer.

    PubMed

    Sasajima, Junpei; Okamoto, Kotaro; Taniguchi, Masato

    2016-01-01

    While the gastric involvement of pancreatic cancer is occasionally observed as the result of direct invasion, hematogenous gastric metastasis is rare. A 72-year-old Japanese male presented with general fatigue, pollakiuria, and thirst. Computed tomography revealed a 4.6-cm solid mass in the pancreatic tail and a 4.2-cm multilocular cystic mass in the pancreatic head with multiple liver and lymphatic metastasis. Notably, two solid masses were detected in the gastric wall of the upper body and the antrum; both were separated from the primary pancreatic cancer and seemed to be located in the submucosal layer. Esophagogastroduodenoscopy revealed a submucosal tumor with a normal mucosa in the posterior wall of the upper body of the stomach, suggesting the gastric hematogenous metastasis of pancreatic cancer. The suspected diagnosis was unresectable pancreatic cancer with multiple metastases that was concomitant with the intraductal papillary mucinous neoplasm of the pancreas. PMID:27403106

  2. [Sacral metastasis simulating aneurysmal bone cyst].

    PubMed

    Sanromán-Álvarez, Pablo; Simal-Julián, Juan Antonio; Miranda-Lloret, Pablo; Pérez-Borredá, Pedro; Botella-Asunción, Carlos

    2014-01-01

    Cystic spinal lesions with characteristic patterns, such as the presence of haematic fluid-fluid levels (H-FFL), have been associated with many tumoral lineages, more frequently with aneurysmal bone cyst (ABC) and exceptionally with metastasis. We present the case of a 60-year-old man with the finding of a sacral cystic bone lesion with H-FFL, with initial suspicion of ABC and confirmed diagnosis of metastasis. The case presented is, to our knowledge, the second case published of spinal cystic bone metastasis with H-FFL pattern with unknown primary tumour at the time of diagnosis and the only one that received resective surgical treatment, achieving pulmonary and metastatic disease control with good quality of life after 1 year of follow up.

  3. Breast cancer metastasis suppressor 1 coordinately regulates metastasis-associated microRNA expression

    PubMed Central

    Edmonds, Mick D.; Hurst, Douglas R.; Vaidya, Kedar S.; Stafford, Lewis J.; Chen, Dongquan; Welch, Danny R.

    2009-01-01

    Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis of multiple tumor types without blocking tumorigenesis. BRMS1 forms complexes with SIN3, histone deacetylases and selected transcription factors that modify metastasis-associated gene expression (e.g., EGFR, OPN, PI4P5K1A, PLAU). microRNA (miRNA) are a recently discovered class of regulatory, noncoding RNA, some of which are involved in neoplastic progression. Based on these data, we hypothesized that BRMS1 may also exert some of its antimetastatic effects by regulating miRNA expression. Micro-RNA arrays were done comparing small RNAs that were purified from metastatic MDA-MB-231 and MDA-MB-435 and their non-metastatic BRMS1-transfected counterparts. miRNA expression changed by BRMS1 were validated using SYBR Green RT-PCR. BRMS1 decreased metastasis-promoting (miR-10b, -373 and -520c) miRNA, with corresponding reduction of their downstream targets (e.g., RhoC which is downstream of miR-10b). Concurrently, BRMS1 increased expression of metastasis suppressing miRNA (miR-146a, -146b and -335). Collectively, these data show that BRMS1 coordinately regulates expression of multiple metastasis-associated miRNA and suggests that recruitment of BRMS1-containing SIN3:HDAC complexes to, as yet undefined, miRNA promoters might be involved in the regulation of cancer metastasis. PMID:19585508

  4. Cranial computed tomographic abnormalities in leptomeningeal metastasis

    SciTech Connect

    Lee, Y.Y.; Glass, J.P.; Geoffray, A.; Wallace, S.

    1984-11-01

    Sixty-four (57.6%) of 111 cancer patients with cerebrospinal fluid cytology positive for malignant cells had cranial computed tomographic (CT) scans within 2 weeks before or after a lumbar puncture. Twenty-two (34.3%) of the 64 had abnormal CT findings indicative of leptomeningeal metastasis. Thirteen (59.6%) of these 22 patients had associated parenchymal metastases. Recognition of leptomeningeal disease may alter the management of patients with parenchymal metastases. Communicating hydrocephalus in cancer patients should be considered to be related to leptomeningeal metastasis until proven otherwise.

  5. Hand metastasis from a sacral chordoma

    PubMed Central

    Kaya, M; Sugita, S; Soma, T; Sasaki, M; Yamashita, T

    2014-01-01

    Chordomas are rare, low grade, malignant tumours derived from the ectopic remnants of the notochord that line the axial skeleton. They are characterised by their slow growth, long disease course and propensity for local relapse. Furthermore, up to 40% of non-cranial chordomas metastasise. We describe the first reported case of a hand metastasis arising from a conventional sacral chordoma after carbon ion radiotherapy. The common occurrence of distant metastasis with chordomas makes it important to perform a systemic examination, in part because their resection might improve patient prognosis. PMID:25350167

  6. Crossing the endothelial barrier during metastasis.

    PubMed

    Reymond, Nicolas; d'Água, Bárbara Borda; Ridley, Anne J

    2013-12-01

    During metastasis, cancer cells disseminate to other parts of the body by entering the bloodstream in a process that is called intravasation. They then extravasate at metastatic sites by attaching to endothelial cells that line blood vessels and crossing the vessel walls of tissues or organs. This Review describes how cancer cells cross the endothelial barrier during extravasation and how different receptors, signalling pathways and circulating cells such as leukocytes and platelets contribute to this process. Identification of the mechanisms that underlie cancer cell extravasation could lead to the development of new therapies to reduce metastasis.

  7. Surviving at a distance: organ specific metastasis

    PubMed Central

    Obenauf, Anna C.; Massagué, Joan

    2015-01-01

    The clinical manifestation of metastasis in a vital organ is the final stage of cancer progression and the main culprit of cancer related mortality. Once established, metastasis is devastating, yet only a small proportion of the cancer cells that leave a tumor succeed at infiltrating, surviving, and ultimately overtaking a distant organ. The bottlenecks that challenge cancer cells in newly invaded microenvironments are organ specific and consequently demand distinct mechanisms for metastatic colonization. Here we review the metastatic traits that allow cancer cells to colonize distinct organ sites. PMID:26693180

  8. Invasive cancer cells and metastasis

    NASA Astrophysics Data System (ADS)

    Mierke, Claudia Tanja

    2013-12-01

    The physics of cancer is a relatively new emerging field of cancer research. In the last decade it has become a focus of biophysical research as well as becoming a novel focus for classical cancer research. This special section of Physical Biology focusing on invasive cancer cells and metastasis (physical oncology) will give greater insight into the different subfields where physical approaches are being applied to cancer research. This focus on the physical aspects of cancer is necessary because novel approaches in the field of genomics and proteomics have not altered the field of cancer research dramatically, due to the fact that few breakthroughs have been made. It is still not understood why some primary tumors metastasize and thus have a worse outcome compared to others that do not metastasize. As biophysicists, we and others suggest that the mechanical properties of the cancer cells, which possess the ability to transmigrate, are quite different compared to non-metastatic and non-invasive cancer cells. Furthermore, we hypothesize that these cancer cells undergo a selection process within the primary tumor that enables them to weaken their cell-cell adhesions and to alter their cell-matrix adhesions in order to be able to cross the outermost boundary of the primary tumor, as well as the surrounding basement membrane, and to invade the connective tissue. This prerequisite may also help the cancer cells to enter blood or lymph vessels, get transported with the vessel flow and form secondary tumors either within the vessel, directly on the endothelium, or in a different organ after crossing the endothelial lining a second time. This special section begins with a paper by Mark F Coughlin and Jeffrey J Fredberg on the changes in cytoskeletal dynamics and nonlinear rheology due to the metastatic capability of cancer cells from different cancer tissue types such as skin, bladder, prostate and kidney [1]. The hypothesis was that the metastatic outcome is impacted by

  9. Powering Tumor Metastasis with Recycled Fuel.

    PubMed

    Hung, Mien-Chie; Yang, Riyao; Sun, Yutong

    2016-09-12

    Receptor tyrosine kinase (RTK) recycling is of critical importance for RTK signaling and cancer, yet the process is poorly understood. In this issue, Ye et al. identify GOLM1 as a cargo adaptor that drives hepatocellular carcinoma metastasis by promoting EGFR recycling and provide insights into how this process is regulated. PMID:27622330

  10. Bone metastasis and the metastatic niche.

    PubMed

    Ren, Guangwen; Esposito, Mark; Kang, Yibin

    2015-11-01

    The bone marrow has been long known to host a unique environment amenable to colonization by metastasizing tumor cells. Yet, the underlying molecular interactions within this specialized microenvironment which give rise to the high incidence of bone metastasis in breast and prostate cancer patients have long remained uncharacterized. With the recent description of the bone metastatic "niche," considerable focus has been placed on understanding how the bone stroma contributes to each step of metastasis. Discoveries within this field have demonstrated that when cancer cells home to the niche in which hematopoietic and mesenchymal stem/progenitor cells normally reside, a bidirectional crosstalk emerges between the tumor cells and the bone metastatic stroma. This communication modulates every step of cancer cell metastasis to the bone, including the initial homing and seeding, formation of micrometastases, outgrowth of macrometastases, and the maintenance of long-term dormancy of disseminated tumor cells in the bone. In clinical practice, targeting the bone metastatic niche is evolving into a promising avenue for the prevention of bone metastatic relapse, therapeutic resistance, and other aspects of cancer progression. Here, we review the current knowledge concerning the role of the bone metastatic niche in bone metastasis.

  11. Altered Tumor-Cell Glycosylation Promotes Metastasis

    PubMed Central

    Häuselmann, Irina; Borsig, Lubor

    2014-01-01

    Malignant transformation of cells is associated with aberrant glycosylation presented on the cell-surface. Commonly observed changes in glycan structures during malignancy encompass aberrant expression and glycosylation of mucins; abnormal branching of N-glycans; and increased presence of sialic acid on proteins and glycolipids. Accumulating evidence supports the notion that the presence of certain glycan structures correlates with cancer progression by affecting tumor-cell invasiveness, ability to disseminate through the blood circulation and to metastasize in distant organs. During metastasis tumor-cell-derived glycans enable binding to cells in their microenvironment including endothelium and blood constituents through glycan-binding receptors – lectins. In this review, we will discuss current concepts how tumor-cell-derived glycans contribute to metastasis with the focus on three types of lectins: siglecs, galectins, and selectins. Siglecs are present on virtually all hematopoietic cells and usually negatively regulate immune responses. Galectins are mostly expressed by tumor cells and support tumor-cell survival. Selectins are vascular adhesion receptors that promote tumor-cell dissemination. All lectins facilitate interactions within the tumor microenvironment and thereby promote cancer progression. The identification of mechanisms how tumor glycans contribute to metastasis may help to improve diagnosis, prognosis, and aid to develop clinical strategies to prevent metastasis. PMID:24592356

  12. Targeting tumor cell motility to prevent metastasis

    PubMed Central

    Palmer, Trenis D.; Ashby, William J.; Lewis, John D.; Zijlstra, Andries

    2011-01-01

    Mortality and morbidity in patients with solid tumors invariably results from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited. In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell-cell adhesion, cell-matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities. PMID:21664937

  13. S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction

    PubMed Central

    Dahlmann, Mathias; Kobelt, Dennis; Walther, Wolfgang; Mudduluru, Giridhar; Stein, Ulrike

    2016-01-01

    The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of β-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success. PMID:27331819

  14. P62: An emerging oncotarget for osteolytic metastasis

    PubMed Central

    Zhang, Jing; Yang, Zuozhang; Dong, Jian

    2016-01-01

    Bone metastasis occurs in the majority of late-stage tumors with poor prognosis. It is mainly classified as osteoblastic metastasis and osteolytic metastasis. The pathogenesis of osteolytic metastasis is a “vicious cycle” between tumor cells and bone cells (primarily the osteoclasts), which is mediated by secretory factors. The P62 adapter protein is a versatile multitasker between tumor cells and bone cells. The overexpression of P62 has been detected among a variety of tumors, playing positive roles in both tumorigenesis and metastasis. Moreover, P62 is an important modulator of the osteoclastogenesis pathway. Therefore, the ability of P62 to modulate tumors and osteoclasts suggests that it may be a feasible oncotarget for bone metastasis, especially for osteolytic metastasis. Recent research has shown that a P62 DNA vaccine triggered effective anti-tumor, anti-metastatic and anti-osteoporotic activities. Growing lines of evidence point to P62 as an emerging oncotarget for osteolytic metastasis. In this review, we outline the different roles of P62 in tumor cells and osteoclasts, focusing on the P62-related signaling pathway in key steps of osteolytic metastasis, including tumorigenesis, metastasis and osteoclastogenesis. Finally, we discuss the newest observations on P62 as an oncotarget for osteolytic metastasis treatment. PMID:26998424

  15. Microenvironmental regulation of tumor progression and metastasis.

    PubMed

    Quail, Daniela F; Joyce, Johanna A

    2013-11-01

    Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

  16. Roadblocks to translational advances on metastasis research.

    PubMed

    Brabletz, Thomas; Lyden, David; Steeg, Patricia S; Werb, Zena

    2013-09-01

    Promising advances in cancer therapy stemming from an increasing understanding of the molecular and genetic underpinnings of the tumorigenic process have been fueled by a strong, determined scientific community, influential patient advocacy groups and committed funding bodies. Despite these efforts, the development of effective drugs to prevent systemic dissemination of cancer cells or to eliminate overt metastasis in secondary organs remains a challenge to both researchers and physicians. In an attempt to tackle the most relevant and timely translational issues, a meeting held in 2012 as a result of a successful partnership between the Volkswagen Foundation and Nature Medicine brought together a group of metastasis research experts to identify the most important hurdles and help create a framework for potential clinical and translational strategies. PMID:24013756

  17. Progression and metastasis of lung cancer.

    PubMed

    Popper, Helmut H

    2016-03-01

    Metastasis in lung cancer is a multifaceted process. In this review, we will dissect the process in several isolated steps such as angiogenesis, hypoxia, circulation, and establishment of a metastatic focus. In reality, several of these processes overlap and occur even simultaneously, but such a presentation would be unreadable. Metastasis requires cell migration toward higher oxygen tension, which is based on changing the structure of the cell (epithelial-mesenchymal transition), orientation within the stroma and stroma interaction, and communication with the immune system to avoid attack. Once in the blood stream, cells have to survive trapping by the coagulation system, to survive shear stress in small blood vessels, and to find the right location for extravasation. Once outside in the metastatic locus, tumor cells have to learn the communication with the "foreign" stroma cells to establish vascular supply and again express molecules, which induce immune tolerance.

  18. Distinctive properties of metastasis-initiating cells

    PubMed Central

    Celià-Terrassa, Toni; Kang, Yibin

    2016-01-01

    Primary tumors are known to constantly shed a large number of cancer cells into systemic dissemination, yet only a tiny fraction of these cells is capable of forming overt metastases. The tremendous rate of attrition during the process of metastasis implicates the existence of a rare and unique population of metastasis-initiating cells (MICs). MICs possess advantageous traits that may originate in the primary tumor but continue to evolve during dissemination and colonization, including cellular plasticity, metabolic reprogramming, the ability to enter and exit dormancy, resistance to apoptosis, immune evasion, and co-option of other tumor and stromal cells. Better understanding of the molecular and cellular hallmarks of MICs will facilitate the development and deployment of novel therapeutic strategies. PMID:27083997

  19. An unusual intracranial metastasis of osteosarcoma.

    PubMed

    Chang, J W; Howng, S L; Sun, Z M; Kuo, T H; Duh, C C

    1994-12-01

    Intracranial metastasis is unusual in osteosarcoma. A case of osteosarcoma was presented with a large intracranial "stone" which was a subdural convexity metastasis. Smaller epidural metastases over other areas were noted also in brain CT scan. Using the radiographs and bone scans, many other lesions at bones, the mediastinum, pleura, perirenal space, and adrenal gland were detected simultaneously. This condition might result from either early metastases or multifocal osteosarcomas. Because many of the above lesion sites were not frequent locations of primary osteosarcoma and had been reported as metastatic targets of osteosarcoma. So the explanation of a very malignant osteosarcoma with early metastases may be more appropriate for this case. The baseball-like tumor in the subdural space with marked compression of the brain surface was grossly totally excised. Histopathologic examination confirmed the diagnosis of osteosarcoma. Postoperatively, the man's condition improved dramatically, though only for two months. He died 5 months later. Reports of such metastatic osteosarcomas are reviewed.

  20. Computational systems biology in cancer brain metastasis.

    PubMed

    Peng, Huiming; Tan, Hua; Zhao, Weiling; Jin, Guangxu; Sharma, Sambad; Xing, Fei; Watabe, Kounosuke; Zhou, Xiaobo

    2016-01-01

    Brain metastases occur in 20-40% of patients with advanced malignancies. A better understanding of the mechanism of this disease will help us to identify novel therapeutic strategies. In this review, we will discuss the systems biology approaches used in this area, including bioinformatics and mathematical modeling. Bioinformatics has been used for identifying the molecular mechanisms driving brain metastasis and mathematical modeling methods for analyzing dynamics of a system and predicting optimal therapeutic strategies. We will illustrate the strategies, procedures, and computational techniques used for studying systems biology in cancer brain metastases. We will give examples on how to use a systems biology approach to analyze a complex disease. Some of the approaches used to identify relevant networks, pathways, and possibly biomarkers in metastasis will be reviewed into details. Finally, certain challenges and possible future directions in this area will also be discussed.

  1. MRI of metastasis-permissive microenvironments

    PubMed Central

    Penet, Marie-France; Chen, Zhihang; Bhujwalla, Zaver M

    2011-01-01

    One of the earliest documented observations of the importance of the microenvironment in metastasis was made by Stephen Paget in 1889. More than a century later, the metastatic cascade remains a major cause of mortality from cancer. Cancer meets the criterion of a successful organization that is able to survive by adapting to changing environments. In fact, the tumor microenvironment and stroma are co-opted and shaped by cancer cells to derive a survival advantage. Cohesive strategies integrating advances in molecular biology and chemistry, with noninvasive multimodality imaging, provide new insights into the role of the tumor microenvironment in promoting metastasis from primary tumors as well as insights into environments that attract and permit cancer cells to establish colonies in distant organs. This article provides an overview of molecular and functional imaging characterization of microenvironments that can promote or permit cancer cells to metastasize and the microenvironmental characteristics of distant metastases. PMID:22044202

  2. Mandibular metastasis of cholangiocarcinoma: A case report

    PubMed Central

    You, Tae Min; Kim, Kee-Deog; Jeong, Ho-Gul

    2015-01-01

    Tumors metastasizing from distant regions to the oral and maxillofacial region are uncommon, comprising only 1%-2% of all malignancies. Cholangiocarcinoma is a malignancy that arises from cholangiocytes, which are epithelial cells that line the bile ducts. These cancers are difficult to diagnose and have a poor prognosis. In this paper, we report a rare case of mandibular metastasis of cholangiocarcinoma diagnosed at the primary site and discuss the radiographic findings observed in this case. PMID:26730373

  3. Pathobiology of cancer metastasis: a short account.

    PubMed

    Feller, Liviu; Kramer, Beverley; Lemmer, Johan

    2012-01-01

    Cancer-initiating cells display aberrant functional and phenotypic characteristics of normal stem cells from which they evolved by accumulation of multiple cytogenetic and/or epigenetic alterations. Signal transduction pathways which are essential for normal stem cell function are abnormally expressed by cancer cells, with a cancer cell phenotype playing an essential role in cancerization and metastasis.Local tumour progression, metastasis and metastatic tumour growth are mediated by direct cell-to-cell and paracrine reciprocal interactions between cancer cells and various stromal cells including fibroblasts, macrophages, bone marrow derived stem cells and progenitor cells. These interactions mediate breakdown of basement membrane barriers and angiogenesis both locally at the invasive front of the primary tumour and at the distant metastatic site; attract primary tumour cells to the candidate metastatic site; and promote proliferation, survival and growth of primary tumour cells and of metastatic cells at their distant site.It is the purpose of this article to highlight the analogies between some of the genetic programs of normal stem cells, and of cancer cells participating in the process of metastasis. PMID:22676510

  4. Bone Metastasis from Renal Cell Carcinoma.

    PubMed

    Chen, Szu-Chia; Kuo, Po-Lin

    2016-01-01

    About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor prognosis. Bone-targeted treatment using bisphosphonate and denosumab can reduce skeletal complications in RCC, but does not cure the disease or improve survival. Elucidating the molecular mechanisms of tumor-induced changes in the bone microenvironment is needed to develop effective treatment. The "vicious cycle" hypothesis has been used to describe how tumor cells interact with the bone microenvironment to drive bone destruction and tumor growth. Tumor cells secrete factors like parathyroid hormone-related peptide, transforming growth factor-β and vascular endothelial growth factor, which stimulate osteoblasts and increase the production of the receptor activator of nuclear factor κB ligand (RANKL). In turn, the overexpression of RANKL leads to increased osteoclast formation, activation and survival, thereby enhancing bone resorption. This review presents a general survey on bone metastasis in RCC by natural history, interaction among the immune system, bone and tumor, molecular mechanisms, bone turnover markers, therapies and healthcare burden. PMID:27338367

  5. Bone Metastasis from Renal Cell Carcinoma

    PubMed Central

    Chen, Szu-Chia; Kuo, Po-Lin

    2016-01-01

    About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor prognosis. Bone-targeted treatment using bisphosphonate and denosumab can reduce skeletal complications in RCC, but does not cure the disease or improve survival. Elucidating the molecular mechanisms of tumor-induced changes in the bone microenvironment is needed to develop effective treatment. The “vicious cycle” hypothesis has been used to describe how tumor cells interact with the bone microenvironment to drive bone destruction and tumor growth. Tumor cells secrete factors like parathyroid hormone-related peptide, transforming growth factor-β and vascular endothelial growth factor, which stimulate osteoblasts and increase the production of the receptor activator of nuclear factor κB ligand (RANKL). In turn, the overexpression of RANKL leads to increased osteoclast formation, activation and survival, thereby enhancing bone resorption. This review presents a general survey on bone metastasis in RCC by natural history, interaction among the immune system, bone and tumor, molecular mechanisms, bone turnover markers, therapies and healthcare burden. PMID:27338367

  6. Metastasis of Prostate Adenocarcinoma to the Testis

    PubMed Central

    Campara, Zoran; Simic, Dejan; Aleksic, Predrag; Spasic, Aleksandar; Milicevic, Snjezana

    2016-01-01

    Introduction: Prostate carcinoma is the most frequently diagnosed carcinoma in the male population. The most typical places of the metastases are pelvic lymphatic glands, bones and lungs, and very rarely it metastasizes into a testis. The prognostic importance of testicular metastasis of prostate cancer is not yet well-known, due to a very few published cases. According to the known facts, it is certain that a metastasis of the prostate carcinoma into a testis is a sign of an advanced disease. Case report: This work presents a 48-year-old patient, to whom an adenocarcinoma of the prostate has been proven by the pathohistological finding of transrectal biopsy, performed due to the elevated level of prostate-specific antigen (PSA). Nine years after the initial diagnosis, due to a gradual rise of PSA and tumorous enlargement of the left testis, left inguinal orchectomy and right orchectomy were performed. Metastatic dissemination of prostate adenocarcinoma into a testis was determined by a pathohistological analysis of the left testis. Conclusion: The metastasis of the prostate carcinoma into a testis, as a rare localization of the metastatic dissemination, after additionally performed orchectomy along with further oncological therapy, can provide a continuation of a good life quality as well as a control of the disease in a longer time period. PMID:27703299

  7. Brain metastasis: new opportunities to tackle therapeutic resistance.

    PubMed

    Seoane, Joan; De Mattos-Arruda, Leticia

    2014-09-12

    Brain metastasis is a devastating complication of cancer with unmet therapeutic needs. The incidence of brain metastasis has been rising in cancer patients and its response to treatment is limited due to the singular characteristics of brain metastasis (i.e., blood-brain-barrier, immune system, stroma). Despite improvements in the treatment and control of extracranial disease, the outcomes of patients with brain metastasis remain dismal. The mechanisms that allow tumor cells to promulgate metastases to the brain remain poorly understood. Further work is required to identify the molecular alterations inherent to brain metastasis in order to identify novel therapeutic targets and explicate the mechanisms of resistance to systemic therapeutics. In this article, we review current knowledge of the unique characteristics of brain metastasis, implications in therapeutic resistance, and the possibility of developing biomarkers to rationally guide the use of targeted agents.

  8. Pulmonary metastasis of giant cell tumor of bones.

    PubMed

    Muheremu, Aikeremujiang; Niu, Xiaohui

    2014-08-20

    Giant cell tumor of bone (GCTB) accounts for 5% of primary skeletal tumors. Although it is considered to be a benign lesion, there are still incidences of pulmonary metastasis. Pulmonary metastasis of GCTB may be affected by tumor grading and localization as well as the age, gender and overall health status of the patient. Patients with local recurrence are more likely to develop pulmonary metastasis of GCTB. High expression of some genes, cytokines and chemokines may also be closely related to the metastatic potential and prognosis of GCTB. The treatment of the primary GCTB is key to the final outcome of the disease, as intralesional curettage has a significantly higher local recurrence and pulmonary metastasis rate than wide resection. However, even patients with pulmonary metastasis seem to have a good prognosis after timely and appropriate surgical resection. It is hoped that with the development of novel surgical methods and drugs, pulmonary metastasis of GCTB can be prevented and treated more effectively.

  9. Skeletal metastasis: treatments, mouse models, and the Wnt signaling

    PubMed Central

    Valkenburg, Kenneth C.; Steensma, Matthew R.; Williams, Bart O.; Zhong, Zhendong

    2013-01-01

    Skeletal metastases result in significant morbidity and mortality. This is particularly true of cancers with a strong predilection for the bone, such as breast, prostate, and lung cancers. There is currently no reliable cure for skeletal metastasis, and palliative therapy options are limited. The Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical target. Several experimental models of skeletal metastasis have been used to find new biomarkers and test new treatments. In this review, we discuss pathologic process of bone metastasis, the roles of the Wnt signaling, and the available experimental models and treatments. PMID:23327798

  10. [Research progress on mechanisms of modern medicine in cancer metastasis].

    PubMed

    Chen, Hui; Qu, Jing-Lian; Gong, Jie-Ning

    2014-08-01

    Cancer metastasis is the most dangerous stage of tumorigenesis and evolution, the primary cause of death in cancer patients. Clinically, more than 60% of cancer patients have found metastasis at the time of examination. Modern medicine has made significant progress on the mechanisms of cancer metastasis in recent years, from the simple "anatomy and machinery" theory forward to the "seed and soil" theory, then to the "microenvironmental" theory and the "cancer stem cell" theory. The emerging "cancer stem cell" theory successfully explains phenomenon such as tumor genetic heterogeneity, anoikis resistance, tumor dormancy, providing more new targets and ideas for the diagnosis and treatment of cancer metastasis.

  11. The molecular biology of pulmonary metastasis.

    PubMed

    Krishnan, Kartik; Khanna, Chand; Helman, Lee J

    2006-05-01

    Curing cancer requires the treatment of metastatic disease. Whether this is a patient with advanced disease and clinically apparent metastases, or if the patient with localized disease is at risk for development of dissemination, failure to control metastasis will result in a poor outcome. Here, we have presented a molecular guide to our current understanding of the processes underlying metastasis. Experimental clinical trials designed to further the understanding of metastasis are often limited by selection of patients with advanced disease. Therefore, our understanding of the processes involved in the metastatic cascade is limited by the availability of comprehensive experimental model systems. The study of metastasis relies most heavily on xenografts, tumors using human cell lines, or tumor tissue that can grow in mice. These models present a limited recapitulation of the patients. Xenograft models require some degree of immunosuppression on the part of the host, because mice with native immune systems will reject transplanted human tumors, preventing their growth. As a result, mice with immune defects ranging from depleted T cells (nude mice) to absent T, B, and NK cells (SCID-Beige) are used as hosts. As the evasion of the immune system is a key function demonstrated by the metastatic cancer cell, xenograft models, by necessity, subvert this step. Furthermore, recent studies have established that angiogenesis in transplanted tumors is different than in native tumors, further highlighting the limitations of these models. With these limitations, studies of metastasis may require development of models of autochthonous tumors, that is, tumors originating in the study animals. A number of cell lines of autochthonous murine tumors have been established that generate metastatic disease after implantation into mice. Moreover, some transgenic animals spontaneously develop metastatic tumors that, although occurring in genetically engineered animals, may represent the

  12. Contemporary approaches for imaging skeletal metastasis

    PubMed Central

    Ulmert, David; Solnes, Lilja; Thorek, Daniel LJ

    2015-01-01

    The skeleton is a common site of cancer metastasis. Notably high incidences of bone lesions are found for breast, prostate, and renal carcinoma. Malignant bone tumors result in significant patient morbidity. Identification of these lesions is a critical step to accurately stratify patients, guide treatment course, monitor disease progression, and evaluate response to therapy. Diagnosis of cancer in the skeleton typically relies on indirect bone-targeted radiotracer uptake at sites of active bone remodeling. In this manuscript, we discuss established and emerging tools and techniques for detection of bone lesions, quantification of skeletal tumor burden, and current clinical challenges. PMID:26273541

  13. Embracing rejection: Immunologic trends in brain metastasis.

    PubMed

    Farber, S Harrison; Tsvankin, Vadim; Narloch, Jessica L; Kim, Grace J; Salama, April K S; Vlahovic, Gordana; Blackwell, Kimberly L; Kirkpatrick, John P; Fecci, Peter E

    2016-07-01

    Brain metastases represent the most common type of brain tumor. These tumors offer a dismal prognosis and significantly impact quality of life for patients. Their capacity for central nervous system (CNS) invasion is dependent upon induced disruptions to the blood-brain barrier (BBB), alterations to the brain microenvironment, and mechanisms for escaping CNS immunosurveillance. In the emerging era of immunotherapy, understanding how metastases are influenced by the immunologic peculiarities of the CNS will be crucial to forging therapeutic advances. In this review, the immunology of brain metastasis is explored. PMID:27622023

  14. Fully Regressive Melanoma: A Case Without Metastasis.

    PubMed

    Ehrsam, Eric; Kallini, Joseph R; Lebas, Damien; Khachemoune, Amor; Modiano, Philippe; Cotten, Hervé

    2016-08-01

    Fully regressive melanoma is a phenomenon in which the primary cutaneous melanoma becomes completely replaced by fibrotic components as a result of host immune response. Although 10 to 35 percent of cases of cutaneous melanomas may partially regress, fully regressive melanoma is very rare; only 47 cases have been reported in the literature to date. AH of the cases of fully regressive melanoma reported in the literature were diagnosed in conjunction with metastasis on a patient. The authors describe a case of fully regressive melanoma without any metastases at the time of its diagnosis. Characteristic findings on dermoscopy, as well as the absence of melanoma on final biopsy, confirmed the diagnosis. PMID:27672418

  15. Monoclonal Antibody Testing for Cancer Metastasis

    NASA Technical Reports Server (NTRS)

    1993-01-01

    Malignant cells are characterized by the ability to invade surrounding normal tissues. Tumor invasion is abetted by proteolytic enzymes that have been correlated with recurrent disease and metastasis. These enzymes are involved in a cascade of proteolytic interactions with other enzymes and inhibitors which allow cancer cells to dissolve surrounding extracellular matrix, thereby enabling the cells to rapidly invade adjacent tissues and migrate to metastatic sites distant from the primary tumor. Among these proteases are the plasminogen activators (PA), collagenase IV, faminase, and in some cases cathepsin D, which together mediate key steps in the invasion process of metastasis. Cells which have the selective advantage for invasion and metastasis are those capable of regulating their proteolytic activity and proliferation. Cells in the process of invasion would be probably down-regulated for proliferation, but subsequent to attachment and adhesion at a distant site, would then be in a proliferative mode, up-regulating DNA replication. Urokinase (uPA) can be present in the tissues in several molecular forms. The inactive proenzyme is a single chain protein (scuPA) that is cleaved at Lys. 158 to form the double chain, high molecular weight active form (HMW-uPA) of 54 kD. A low molecular weight form (LMW-uPA) can also be produced by cleavage of the HMW-U PA at Lys. 135 - Lys. 136 giving a 35 kD active enzyme. Recently, it has been shown that the HMW active form of urokinase, bound to the tumor cell membrane, is responsible for the local lysis of the extracellular matrix, hence the tissue invasion mechanism for metastasis (Andreasen et al, 19861. Receptor- (membrane) bound uPA is twice as efficient (catalytically) as free fluid-phase uPA. Tho unbound uPA and the LMW form is not responsible for most of the local dissolution of extracellular matrix in the immediate vicinity of the metastatic tumor cell. High levels of urokinase (greater than 3.49 ng/mg of total protein

  16. Orbital Metastasis of Multiple Myeloma: Case Report

    PubMed Central

    Vatansever, Mustafa; Bozkurt, Fatma Merve; Dinç, Erdem; Yılmaz, Eda Bengi; Nayir, Erdinç; Sarı, Ayşe Ayça; Yıldırım, Özlem; Kara, Tuba

    2016-01-01

    A 68-year-old woman with a history of multiple myeloma presented to the clinic with pain and vision loss in her right eye. Proptosis was observed in her right eye and eye movements were restricted in all directions. Best corrected visual acuity was 3/10 in her right eye. On biomicroscopic examination, hyperemia and subconjunctival hemorrhage were present. Fundus examination of the right eye revealed optic disc edema and choroidal folds. In magnetic resonance imaging two orbital masses were detected. Based on the patient’s history and ocular examination, we evaluated the masses as orbital metastasis of multiple myeloma. Palliative radiotherapy was recommended. PMID:27800278

  17. Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis.

    PubMed

    Okugawa, Yoshinaga; Toiyama, Yuji; Hur, Keun; Toden, Shusuke; Saigusa, Susumu; Tanaka, Koji; Inoue, Yasuhiro; Mohri, Yasuhiko; Kusunoki, Masato; Boland, C Richard; Goel, Ajay

    2014-12-01

    The prognosis of gastric cancer (GC) patients with peritoneal dissemination remains poor, and a better understanding of the underlying mechanisms is critical for the development of new treatments that will improve survival in these patients. This study aimed to clarify the clinical and biological role of two key metastasis-associated long non-coding RNAs (lncRNAs) in GC. We analyzed the expression levels of two lncRNAs-Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX-Antisense Intergenic RNA (HOTAIR)-by real-time reverse transcription PCR in 300 gastric tissues (150 GC and 150 adjacent normal mucosa), and in seven GC cell lines. Functional characterization for the role of HOTAIR in GC was performed by small interfering RNA (siRNA) knockdown, followed by series of in-vitro and in-vivo experiments. Expression of both lncRNAs was significantly higher in cancerous tissues than in corresponding normal mucosa, and higher expression of these lncRNAs significantly correlated with peritoneal metastasis in GC patients. In addition, elevated HOTAIR expression emerged both as an independent prognostic and risk factor for peritoneal dissemination. SiRNA knockdown of HOTAIR in GC cells significantly inhibited cell proliferation, migration and invasion, but concurrently enhanced the anoikis rate in transfected cells. In an in vivo assay, HOTAIR siRNA-transfected MKN45 cells injected into nude mice inhibited the growth of xenograft tumors and peritoneal metastasis compared with controls. Our data provide novel evidence for the biological and clinical significance of HOTAIR expression as a potential biomarker for identifying patients with peritoneal metastasis, and as a novel therapeutic target in patients with gastric neoplasia.

  18. Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis

    PubMed Central

    Okugawa, Yoshinaga; Toiyama, Yuji; Hur, Keun; Toden, Shusuke; Saigusa, Susumu; Tanaka, Koji; Inoue, Yasuhiro; Mohri, Yasuhiko; Kusunoki, Masato; Boland, C.Richard; Goel, Ajay

    2014-01-01

    The prognosis of gastric cancer (GC) patients with peritoneal dissemination remains poor, and a better understanding of the underlying mechanisms is critical for the development of new treatments that will improve survival in these patients. This study aimed to clarify the clinical and biological role of two key metastasis-associated long non-coding RNAs (lncRNAs) in GC. We analyzed the expression levels of two lncRNAs—Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX-Antisense Intergenic RNA (HOTAIR)—by real-time reverse transcription PCR in 300 gastric tissues (150 GC and 150 adjacent normal mucosa), and in seven GC cell lines. Functional characterization for the role of HOTAIR in GC was performed by small interfering RNA (siRNA) knockdown, followed by series of in-vitro and in-vivo experiments. Expression of both lncRNAs was significantly higher in cancerous tissues than in corresponding normal mucosa, and higher expression of these lncRNAs significantly correlated with peritoneal metastasis in GC patients. In addition, elevated HOTAIR expression emerged both as an independent prognostic and risk factor for peritoneal dissemination. SiRNA knockdown of HOTAIR in GC cells significantly inhibited cell proliferation, migration and invasion, but concurrently enhanced the anoikis rate in transfected cells. In an in vivo assay, HOTAIR siRNA-transfected MKN45 cells injected into nude mice inhibited the growth of xenograft tumors and peritoneal metastasis compared with controls. Our data provide novel evidence for the biological and clinical significance of HOTAIR expression as a potential biomarker for identifying patients with peritoneal metastasis, and as a novel therapeutic target in patients with gastric neoplasia. PMID:25280565

  19. Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis

    PubMed Central

    Pavlovic, Milica; Arnal-Estapé, Anna; Rojo, Federico; Bellmunt, Anna; Tarragona, Maria; Guiu, Marc; Planet, Evarist; Garcia-Albéniz, Xabier; Morales, Mónica; Urosevic, Jelena; Gawrzak, Sylwia; Rovira, Ana; Prat, Aleix; Nonell, Lara; Lluch, Ana; Jean-Mairet, Joël; Coleman, Robert; Albanell, Joan

    2015-01-01

    Background: There are currently no biomarkers for early breast cancer patient populations at risk of bone metastasis. Identification of mediators of bone metastasis could be of clinical interest. Methods: A de novo unbiased screening approach based on selection of highly bone metastatic breast cancer cells in vivo was used to determine copy number aberrations (CNAs) associated with bone metastasis. The CNAs associated with bone metastasis were examined in independent primary breast cancer datasets with annotated clinical follow-up. The MAF gene encoded within the CNA associated with bone metastasis was subjected to gain and loss of function validation in breast cancer cells (MCF7, T47D, ZR-75, and 4T1), its downstream mechanism validated, and tested in clinical samples. A multivariable Cox cause-specific hazard model with competing events (death) was used to test the association between 16q23 or MAF and bone metastasis. All statistical tests were two-sided. Results: 16q23 gain CNA encoding the transcription factor MAF mediates breast cancer bone metastasis through the control of PTHrP. 16q23 gain (hazard ratio (HR) for bone metastasis = 14.5, 95% confidence interval (CI) = 6.4 to 32.9, P < .001) as well as MAF overexpression (HR for bone metastasis = 2.5, 95% CI = 1.7 to 3.8, P < .001) in primary breast tumors were specifically associated with risk of metastasis to bone but not to other organs. Conclusions: These results suggest that MAF is a mediator of breast cancer bone metastasis. 16q23 gain or MAF protein overexpression in tumors may help to select patients at risk of bone relapse. PMID:26376684

  20. Solitary Spinal Epidural Metastasis from Gastric Cancer

    PubMed Central

    Sako, Taisei; Iida, Yasuaki; Yokoyama, Yuichirou; Tsuge, Shintaro; Hasegawa, Keiji; Wada, Akihito; Mikami, Tetsuo

    2016-01-01

    Solitary epidural space metastasis of a malignant tumor is rare. We encountered a 79-year-old male patient with solitary metastatic epidural tumor who developed paraplegia and dysuria. The patient had undergone total gastrectomy for gastric cancer followed by chemotherapy 8 months priorly. The whole body was examined for suspected metastatic spinal tumor, but no metastases of the spine or important organs were observed, and a solitary mass was present in the thoracic spinal epidural space. The mass was excised for diagnosis and treatment and was histopathologically diagnosed as metastasis from gastric cancer. No solitary metastatic epidural tumor from gastric cancer has been reported in English. Among the Japanese, 3 cases have been reported, in which the outcome was poor in all cases and no definite diagnosis could be made before surgery in any case. Our patient developed concomitant pneumonia after surgery and died shortly after the surgery. When a patient has a past medical history of malignant tumor, the possibility of a solitary metastatic tumor in the epidural space should be considered. PMID:27703825

  1. [Bilateral testicular metastasis of cancer of the prostate].

    PubMed

    el Moussaoui, A; Sarf, I; Dakir, M; Zamiati, S; Benjelloun, S

    1997-01-01

    Testicular metastasis of prostate cancer rarely occurs. Bilateral localization is exceptional. We report a new case of prostate adenocarcinoma with bilateral testicular metastasis. The diagnosis was made on clinical and ultrasonic arguments, and confirmed on the pathological specimen. Treatment consisted in a bilateral orchidectomy, associated with nonsteroid androgens.

  2. AACR centennial series: the biology of cancer metastasis: historical perspective.

    PubMed

    Talmadge, James E; Fidler, Isaiah J

    2010-07-15

    Metastasis resistant to therapy is the major cause of death from cancer. Despite almost 200 years of study, the process of tumor metastasis remains controversial. Stephen Paget initially identified the role of host-tumor interactions on the basis of a review of autopsy records. His "seed and soil" hypothesis was substantiated a century later with experimental studies, and numerous reports have confirmed these seminal observations. An improved understanding of the metastatic process and the attributes of the cells selected by this process is critical for the treatment of patients with systemic disease. In many patients, metastasis has occurred by the time of diagnosis, so metastasis prevention may not be relevant. Treating systemic disease and identifying patients with early disease should be our goal. Revitalized research in the past three decades has focused on new discoveries in the biology of metastasis. Even though our understanding of molecular events that regulate metastasis has improved, the contributions and timing of molecular lesion(s) involved in metastasis pathogenesis remain unclear. Review of the history of pioneering observations and discussion of current controversies should increase understanding of the complex and multifactorial interactions between the host and selected tumor cells that contribute to fatal metastasis and should lead to the design of successful therapy.

  3. Lung cancer metastasis presenting as a solitary skull mass

    PubMed Central

    Turner, Ryan C.; Lucke-Wold, Brandon P.; Hwang, Roy; Underwood, Bill D.

    2016-01-01

    Lung cancer has been well documented to spread to bone and the axial skeleton after metastasis to adjacent organs. Bony metastasis is not, however, the typical presenting manifestation. The differential diagnosis for a tissue mass on the skull should warrant a workup for metastatic disease. Bony metastasis plays an important role in treatment and disease management. We report an exceptionally rare case of stage IV lung adenocarcinoma that presented with a solitary skull metastasis and a significant soft-tissue component. The lesion was treated by excision via craniotomy and subsequent medical management of the adenocarcinoma. This case illustrates a very rare presentation of lung adenocarcinoma and also represents what the authors believe to be the first report of a solitary skull mass originating from a lung primary. We also present a review of the literature surrounding bony metastasis to the skull and implications for patient care. PMID:27340229

  4. Lung cancer metastasis presenting as a solitary skull mass.

    PubMed

    Turner, Ryan C; Lucke-Wold, Brandon P; Hwang, Roy; Underwood, Bill D

    2016-01-01

    Lung cancer has been well documented to spread to bone and the axial skeleton after metastasis to adjacent organs. Bony metastasis is not, however, the typical presenting manifestation. The differential diagnosis for a tissue mass on the skull should warrant a workup for metastatic disease. Bony metastasis plays an important role in treatment and disease management. We report an exceptionally rare case of stage IV lung adenocarcinoma that presented with a solitary skull metastasis and a significant soft-tissue component. The lesion was treated by excision via craniotomy and subsequent medical management of the adenocarcinoma. This case illustrates a very rare presentation of lung adenocarcinoma and also represents what the authors believe to be the first report of a solitary skull mass originating from a lung primary. We also present a review of the literature surrounding bony metastasis to the skull and implications for patient care. PMID:27340229

  5. Endometrial metastasis of colorectal cancer with coincident endometrial adenocarcinoma

    PubMed Central

    Colling, Richard; Lopes, Tito; Das, Nagiindra; Mathew, Joe

    2010-01-01

    Metastasis to the uterine corpus is uncommon and secondary colorectal tumours of the endometrium are rare. We describe a uterine tumour with components of both primary endometrial and metastatic colorectal carcinomata. In this case, a 72-year-old obese woman presented with a 2-week history of postmenopausal bleeding per vaginum and weight loss. She had an abdominoperineal resection 3 years previously for a Dukes stage B rectal carcinoma. A transvaginal ultrasonography showed a thickened endometrium. Histology immunophenotyping showed a CK7+, CK20+, CA125− and CEA+ colorectal metastasis (a profile consistent with her previous cancer) associated with a primary CK7+, CK20−, CA125+ and CEA− endometroid endometrial adenocarcinoma. We conclude this represents endometrial metastasis of colorectal carcinoma with coincident primary endometrial adenocarcinoma. We speculate as to whether the endometrial carcinoma arose de novo or was induced by the colorectal metastasis, or whether the primary endometrial tumour provided a fertile site for the colorectal metastasis. PMID:22791861

  6. Choroid Melanoma Metastasis to Spine: A Rare Case Report

    PubMed Central

    Mandaliya, Hiren; Singh, Nandini; George, Sanila; George, Mathew

    2016-01-01

    Metastatic choroid melanoma is a highly malignant disease with a limited life expectancy. The liver is the most common site for metastasis of uveal melanoma followed by lung, bone, skin, and subcutaneous tissue. Metastasis from choroidal melanoma usually occurs within the first five years of treatment for primary tumours. Metastatic choroid melanoma to the spine/vertebrae is extremely rare. We report the first case of spinal metastasis from choroid melanoma in a 61-year-old man who had been treated for primary ocular melanoma three years earlier with radioactive plaque brachytherapy. Synchronously, at the time of metastasis, he was also diagnosed as having a new primary lung adenocarcinoma as well. The only other case reported on vertebral metastasis from malignant melanoma of choroid in literature in which primary choroid melanoma was enucleated. PMID:26989537

  7. Bone marrow metastasis presenting as bicytopenia originating from hepatocellular carcinoma

    PubMed Central

    Hong, Young Mi; Yoon, Ki Tae; Cho, Mong; Kang, Dae Hwan; Kim, Hyung Wook; Choi, Cheol Woong; Park, Su Bum; Heo, Jeong; Woo, Hyun Young; Lim, Won; Bakhtiar UI Islam, SM

    2016-01-01

    The bone is a common site for metastasis in hepatocellular carcinoma (HCC). However, bone marrow metastasis from HCC is rarely reported, and its frequency is unclear. Here we report a rare case of bone marrow metastasis that presented as bicytopenia originating from HCC without bone metastasis. A 58-year-old man was admitted for investigation of a liver mass with extensive lymph node enlargement that was detected when examining his general weakness and weight loss. Laboratory findings revealed anemia, thrombocytopenia, mild elevated liver enzymes, normal prothrombin time percentage and high levels of tumor markers (α-fetoprotein and des-γ-carboxyprothrombin). Abdominal computed tomography showed multiple enhanced masses in the liver and multiple enlarged lymph nodes in the abdomen. A bone marrow biopsy revealed only a few normal hematopoietic cells and abundant tumor cells. Despite its rarity, bone marrow metastasis should always be suspected in HCC patients even if accompanied by cirrhosis. PMID:27184470

  8. [Thyroid metastasis due to right colonic carcinoma].

    PubMed

    Rauber, E; Pancrazio, F; Spivach, A; Stanta, G

    1998-12-01

    Clinical evident metastases to the thyroid gland are rarely found antemortem. A case of a 62 year-old man with a history of right colonic carcinoma, who presented a mass in the right lobe of his thyroid gland one year after the removal of a metachronous metastasis in his right lung, is presented. The tumour of the thyroid was found to be metastatic adenocarcinoma from his previous colonic cancer. The clinical finding of metastases to the thyroid gland is rare, particularly from a colorectal primary neoplasm. However, the possibility of a tumour of the thyroid gland representing a secondary malignancy is to be considered in any patient with a prior history of cancer.

  9. Bone metastasis: mechanisms and therapeutic opportunities

    PubMed Central

    Suva, Larry J.; Washam, Charity; Nicholas, Richard W.; Griffin, Robert J.

    2011-01-01

    The skeleton is one of the most common sites for metastatic cancer, and tumors arising from the breast or prostate possess an increased propensity to spread to this site. The growth of disseminated tumor cells in the skeleton requires tumor cells to inhabit the bone marrow, from which they stimulate local bone cell activity. Crosstalk between tumor cells and resident bone and bone marrow cells disrupts normal bone homeostasis, which leads to tumor growth in bone. The metastatic tumor cells have the ability to elicit responses that stimulate bone resorption, bone formation or both. The net result of these activities is profound skeletal destruction that can have dire consequences for patients. The molecular mechanisms that underlie these painful and often incurable consequences of tumor metastasis to bone are beginning to be recognized, and they represent promising new molecular targets for therapy. PMID:21200394

  10. Exercise, natural immunity, and tumor metastasis.

    PubMed

    Hoffman-Goetz, L

    1994-02-01

    Exercise has been shown to reduce the growth of primary tumors and to enhance certain aspects of host natural immunity. The question of whether these are independent phenomena or are casually related has not been systematically evaluated. This paper presents information concerning the methodological difficulties in studying proposed relationships between exercise and cancer, focusing specifically on tumor metastasis, the process by which malignant cells disseminate to distant organs and establish new colonies. This paper also focuses on how natural immune processes and tumor cells exert bidirectional influences on each other. It is suggested that the direction of the impact of exercise on the control of metastatic spread of neoplastic cells will reflect, in part, the sensitivity of the specific tumor to cytolysis by natural immune mechanisms, the route of dissemination, the timing of exercise relative to tumor exposure, and whether exercise acts as a distress or eustress state.

  11. Pinworm infection masquerading as colorectal liver metastasis

    PubMed Central

    Roberts, KJ; Hubscher, S; Mangat, K; Sutcliffe, R; Marudanayagam, R

    2012-01-01

    Enterobius vermicularis is responsible for a variety of diseases but rarely affects the liver. Accurate characterisation of suspected liver metastases is essential to avoid unnecessary surgery. In the presented case, following a diagnosis of rectal cancer, a solitary liver nodule was diagnosed as a liver metastasis due to typical radiological features and subsequently resected. At pathological assessment, however, a necrotic nodule containing E vermicularis was identified. Solitary necrotic nodules of the liver are usually benign but misdiagnosed frequently as malignant due to radiological features. It is standard practice to diagnose colorectal liver metastases solely on radiological evidence. Without obtaining tissue prior to liver resection, misdiagnosis of solitary necrotic nodules of the liver will continue to occur. PMID:22943320

  12. Advances in cancer pain from bone metastasis

    PubMed Central

    Zhu, Xiao-Cui; Zhang, Jia-Li; Ge, Chen-Tao; Yu, Yuan-Yang; Wang, Pan; Yuan, Ti-Fei; Fu, Cai-Yun

    2015-01-01

    With the technological advances in cancer diagnosis and treatment, the survival rates for patients with cancer are prolonged. The issue of figuring out how to improve the life quality of patients with cancer has become increasingly prominent. Pain, especially bone pain, is the most common symptom in malignancy patients, which seriously affects the life quality of patients with cancer. The research of cancer pain has a breakthrough due to the development of the animal models of cancer pain in recent years, such as the animal models of mouse femur, humerus, calcaneus, and rat tibia. The establishment of several kinds of animal models related to cancer pain provides a new platform in vivo to investigate the molecular mechanisms of cancer pain. In this review, we focus on the advances of cancer pain from bone metastasis, the mechanisms involved in cancer pain, and the drug treatment of cancer pain in the animal models. PMID:26316696

  13. Adrenal Metastasis from Uterine Papillary Serous Carcinoma

    PubMed Central

    Lubana, Sandeep Singh; Singh, Navdeep; Tuli, Sandeep S.; Seligman, Barbara

    2016-01-01

    Patient: Female, 60 Final Diagnosis: UPSC with adrenal metastasis Symptoms: Post menopausal bleeding Medication: — Clinical Procedure: Adrenalectomy Specialty: Oncology Objective: Rare disease Background: Uterine papillary serous carcinoma (UPSC) is a highly malignant form of endometrial cancer with a high propensity for metastases and recurrences even when there is minimal or no myometrial invasion. It usually metastasizes to the pelvis, retroperitoneal lymph nodes, upper abdomen, and peritoneum. However, adrenal metastases from UPSC is extremely rare. Here, we present a case of UPSC with adrenal metastasis that occurred 6 years after the initial diagnosis. Case Report: A 60-year-old woman previously diagnosed with uterine papillary serous carcinoma at an outside facility presented in September of 2006 with postmenopausal bleeding. She underwent comprehensive surgical staging with FIGO (International Federation of Gynecology and Obstetrics) stage 2. Post-operatively, the patient was treated with radiation and chemotherapy. The treatment was completed in April of 2007. The patient had no evidence of disease until July 2009 when she was found to have a mass highly suspicious for malignancy. Subsequently, she underwent right upper lobectomy. The morphology of the carcinoma was consistent with UPSC. She refused chemotherapy due to a previous history of chemotherapy-induced neuropathy. The patient was followed up with regular computed tomography (CT) scans. In October 2012 a new right adrenal nodule was seen on CT, which showed intense metabolic uptake on positron emission tomography (PET)/CT scan. The patient underwent right adrenalectomy. Pathology of the surgical specimen was consistent with UPSC. Conclusions: UPSC is an aggressive variant of endometrial cancer associated with high recurrence rate and poor prognoses. Long-term follow-up is needed because there is a possibility of late metastases, as in this case. PMID:27117594

  14. Hand1 overexpression inhibits medulloblastoma metastasis.

    PubMed

    Asuthkar, Swapna; Guda, Maheedhara R; Martin, Sarah E; Antony, Reuben; Fernandez, Karen; Lin, Julian; Tsung, Andrew J; Velpula, Kiran K

    2016-08-19

    Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current treatment includes surgery, radiation and chemotherapy. However, ongoing treatment in patients is further classified according to the presence or absence of metastasis. Since metastatic medulloblastoma are refractory to current treatments, there is need to identify novel biomarkers that could be used to reduce metastatic potential, and more importantly be targeted therapeutically. Previously, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus. We further demonstrated that uPAR protein act as cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand1. Among the histological subtypes classical and desmoplastic subtypes account for the majority while large cell/anaplastic variant is most commonly associated with metastatic disease. In this present study using immunohistochemical approach and patient data mining for the first time, we demonstrated that Hand1 expression is observed to be downregulated in all the subtypes of medulloblastoma. Previously we showed that Hand1 overexpression regulated medulloblastoma angiogenesis and here we investigated the role of Hand1 in the context of Epithelial-Mesenchymal Transition (EMT). Moreover, UW228 and D283 cells overexpressing Hand1 demonstrated decreased-expression of mesenchymal markers (N-cadherin, β-catenin and SOX2); metastatic marker (SMA); and increased expression of epithelial marker (E-cadherin). Strikingly, human pluripotent stem cell antibody array showed that Hand1 overexpression resulted in substantial decrease in pluripotency markers (Nanog, Oct3/4, Otx2, Flk1) suggesting that Hand1 expression may be essential to attenuate the EMT and our findings underscore a novel role for Hand1 in medulloblastoma metastasis.

  15. Anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis.

    PubMed

    Pomeraniec, I J; Dallapiazza, R F; Sumner, H M; Lopes, M B; Shaffrey, C I; Smith, J S

    2015-12-01

    We present a rare extramedullary ependymoma with diffuse spinal metastatic disease, and review the previous reports of extramedullary spinal ependymomas. Ependymomas are the most common intramedullary spinal cord tumor in adults. These tumors rarely present as extramedullary masses. We treated a 23-year-old man with a history of progressive neck, shoulder and arm pain, with sensory and motor symptoms in the C7 dermatome. MRI of the cervical spine demonstrated a ventral contrast-enhancing lesion with evidence of enhancement along the dura and spinal cord of the upper cervical spine, thoracic spine, and cauda equina. He underwent a tumor debulking procedure without complications. Following surgery, he received craniospinal radiation to treat the remaining tumor and diffuse leptomeningeal disease. The final pathology of the tumor revealed that is was a World Health Organization Grade III anaplastic ependymoma. At the 1 year follow-up, the patient had stable imaging and had returned to his preoperative functional status. Of the 19 reported patients with primary intradural, extramedullary spinal ependymomas, two had extradural components and seven had anaplastic grades. Only one tumor with an anaplastic grade resulted in metastatic disease, but without spinal recurrence. To our knowledge, this is the first report of an intradural, extramedullary spinal ependymoma with an anaplastic grade, presenting with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. Similar to the treatment of intramedullary ependymomas with metastasis, this patient underwent an aggressive debulking procedure followed by radiation therapy to the entire neuroaxis. PMID:26601808

  16. Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis.

    PubMed

    Wu, Zhen-Zhen; Chen, Li-Shan; Zhou, Rui; Bin, Jian-Ping; Liao, Yu-Lin; Liao, Wang-Jun

    2016-08-01

    Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer (GC), MACC1 has been shown to be involved in oncogenesis and tumor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelial-to-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry (VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment. PMID:27547006

  17. Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis

    PubMed Central

    Wu, Zhen-Zhen; Chen, Li-Shan; Zhou, Rui; Bin, Jian-Ping; Liao, Yu-Lin; Liao, Wang-Jun

    2016-01-01

    Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer (GC), MACC1 has been shown to be involved in oncogenesis and tumor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelial-to-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry (VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment. PMID:27547006

  18. Serpine2, a potential novel target for combating melanoma metastasis

    PubMed Central

    Wu, Qi Wei

    2016-01-01

    Early stages of melanoma can be treated by surgical resection of tumor, but there is still no effective treatment once it is progressed to metastatic phases. Although growing family of both metastasis promoting and metastasis suppressor genes have been reported, the molecular mechanisms governing melanoma metastatic cascade are still not completely understood. Therefore, defining the molecules that govern melanoma metastasis may aid the development of more effective therapeutic strategies for combating cancer. In the present study, we found that Serpin Peptidase Inhibitor 2, Serpine2 was involved in the metastasis of melanoma cells. The requirement of Serpine2 in the migration of melanoma cells was confirmed by gene silencing and over-expression in vitro. Moreover, down-regulation of Serpine2 expression strikingly inhibited melanoma cellular metastasis in vivo. Finally, we found that Serpine2 promotes melanoma metastasis through the glycogen synthesis kinase 3β, GSK-3β signaling pathway. To conclude, our findings suggested a novel mechanism underlying the metastasis of melanoma cells which might serve as a new intervention target for the treatment of melanoma. PMID:27347308

  19. A proposed classification system for liver metastasis from colorectal carcinoma.

    PubMed

    Petrelli, N J; Bonnheim, D C; Herrera, L O; Mittelman, A

    1984-04-01

    A proposed classification system for liver metastasis from colorectal carcinoma is presented. This proposed system utilizes the prognostic factors of the extent of hepatic involvement by metastasis at the time of laparotomy, performance status, preoperative serum alkaline phosphatase level, and the presence or absence of extrahepatic intraabdominal disease at the time of laparotomy. Because of the several different modes of treatment for liver metastasis from colorectal carcinoma, it is necessary that a liver classification system be adopted so that different treatment groups will be comparable. The proposed system utilizes the extent of hepatic involvement by metastasis at laparotomy with a division into three subsets of patients described by a Roman numeral. Roman numeral I represents less than or equal to 25 per cent involvement of the liver by metastasis; Roman numeral II represents greater than 25 per cent but less than or equal to 50 per cent involvement by liver metastasis, and Roman numeral III represents greater than 50 per cent involvement by liver metastasis. An Arabic subscript number is used to describe the patients' performance status. Alkaline phosphatase levels are described by a subscript letter with a representing less than two times normal alkaline phosphatase, b representing greater than two times, but less than four times normal levels, and c representing greater than four times normal levels. At the time of laparotomy extrahepatic intra-abdominal disease is represented by the superscript letter E. PMID:6714032

  20. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

    PubMed

    Wang, Hui; Liu, Xiufei; Long, Min; Huang, Yi; Zhang, Linlin; Zhang, Rui; Zheng, Yi; Liao, Xiaoyu; Wang, Yuren; Liao, Qian; Li, Wenjie; Tang, Zili; Tong, Qiang; Wang, Xiaocui; Fang, Fang; Rojo de la Vega, Montserrat; Ouyang, Qin; Zhang, Donna D; Yu, Shicang; Zheng, Hongting

    2016-04-13

    Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis. PMID:27075625

  1. Cigarette Smoking and Risk of Lung Metastasis from Esophageal Cancer

    PubMed Central

    Abrams, Julian A.; Lee, Paul C.; Port, Jeffrey L.; Altorki, Nasser K.; Neugut, Alfred I.

    2008-01-01

    Background While extensive research has explored the impact of environmental factors on the etiology of specific cancers, the influence of exposures such as smoking on risk of site-specific metastasis is unknown. We investigated the association of cigarette smoking with lung metastasis in esophageal cancer. Methods We performed a case-control study of esophageal cancer patients from two centers, comparing cases with lung metastases to controls without lung metastases. Information was gathered from medical records on smoking history, imaging results, site(s) of metastasis, and other patient and tumor characteristics. We used logistic regression to assess association. Results We identified 354 esophageal cancer cases; smoking status was known in 289 (82%). Among patients with lung metastases, 73.6% (39/53) were ever smokers, versus 47.8% (144/301) of patients without lung metastases (p=0.001) (summary OR 2.52, 95%CI 1.17-5.45; stratified by histology). Smoking was associated with a nonsignificant increased adjusted odds of lung metastasis (OR 1.89, 95%CI 0.80-4.46). Upper esophageal subsite (OR 4.71, 95%CI 1.20-18.5) but not histology (squamous OR 0.65,95%CI 0.27-1.60) was associated with lung metastasis. Compared to the combined never/unknown smoking status group, smoking was associated with a significantly increased odds of lung metastasis (OR 2.35, 95%CI 1.11-4.97). There was no association between liver metastasis and smoking (OR 0.88, 95%CI 0.42-1.83) Conclusions Smoking is associated with increased odds of lung metastasis from esophageal cancer, and this relationship appears to be site-specific. Future studies are needed to determine whether smoking affects the tumor cell or the site of metastasis, and whether this changes the survival outcome. PMID:18843013

  2. Elevation of serum acid phosphatase in cancers with bone metastasis

    SciTech Connect

    Tavassoli, M.; Rizo, M.; Yam, L.T.

    1980-05-01

    In patients with nonprostatic cancer, serum acid phosphatase activity is usually elevated when bone metastasis is present but not when bone metastasis is absent. The fraction responsible for serum enzyme elevation is a normal component of serum; it appears in gel electrophoresis as band 5; and is tartrate-resistant. It is suggested that the origin of acid phosphatase elevation is bone osteoclasts rather than cancer tissue, as is the case with prostatic carcinoma. Determination of serum acid phosphatase activity may be useful in the detection of bone metastasis.

  3. The cofilin pathway in breast cancer invasion and metastasis

    PubMed Central

    Wang, Weigang; Eddy, Robert; Condeelis, John

    2014-01-01

    Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis. PMID:17522712

  4. Cutaneous metastasis: An unusual presenting feature of urologic malignancies

    PubMed Central

    Menon, Arun Ramdas; Thomas, Anju Sussanna; Suresh, Nivedita; Shashidhar, Shashank Malagi

    2016-01-01

    Urological malignancies are well known for their ability to metastasize widely. The incidence of cutaneous metastasis from all urologic malignancies has been reported to be 0.73–1.3% with the primary most commonly being renal cell carcinoma followed by carcinoma bladder, adenocarcinoma prostate, and testicular germ cell tumor in decreasing order of frequency. Metastasis to the skin is unusual and has been predominantly reported as a late manifestation of the disease. We describe two patients with urologic malignancies who had cutaneous metastasis as their initial presenting feature. PMID:27453667

  5. Combined Therapy for Distant Metastasis of Sacral Chordoma

    PubMed Central

    Özkal, Birol; Yaldız, Can; Temiz, Peyker; Temiz, Cüneyt

    2015-01-01

    Chordomas are known as rare primary malign tumours that have formed from primitive notochord remains. Sacral chordomas grow slowly but locally and aggressively. Chordomas are locally invasive and have low tendency to metastasis and have a poor prognosis in long-term follow-up. Metastasis may be seen in a rate of 5–40% of the chordomas. Metastasis of chordomas is common in liver, lung, lymph nodes, peritoneum, and brain. The treatment approaches, including surgery, have been discussed in the literature before. Susceptibility to radiotherapy and chemotherapy is controversial in these tumours. The success of surgical treatment affects survival directly. In this report, we will report a sacral chordoma case in which an intraperitoneal distant metastasis occurred and discuss the surgical approach. PMID:25649759

  6. Development of Individualized Anti-Metastasis Strategies by Engineering Nanomedicines

    PubMed Central

    He, Qianjun; Guo, Shengrong; Qian, Zhiyong; Chen, Xiaoyuan

    2015-01-01

    Metastasis is deadly and also tough to treat as it is much more complicated than the primary tumour. Anti-metastasis approaches available so far are far from being optimal. A variety of nanomedicine formulas provide a plethora of opportunities for developing new strategies and means for tackling metastasis. It should be noted that individualized anti-metastatic nanomedicines are different from common anti-cancer nanomedicines as they specifically target different populations of malignant cells. This review briefly introduces the features of the metastatic cascade, and proposes a series of nanomedicine-based anti-metastasis strategies aiming to block each metastatic step. Moreover, we also concisely introduce the advantages of several promising nanoparticle platforms and their potential for constructing state-of-the-art individualized anti-metastatic nanomedicines. PMID:26056688

  7. Imaging TGFβ Signaling in Mouse Models of Cancer Metastasis.

    PubMed

    Kang, Yibin

    2016-01-01

    Metastatic spread of cancer cells from the primary tumors to distant vital organs, such as lung, liver, brain, and bone, is responsible for the majority of cancer-related deaths. Development of metastatic lesions is critically dependent on the interaction of tumor cells with the stromal microenvironment. As a multifunctional paracrine signaling factor that is abundantly produced by both tumor and stromal cells, TGFβ has been well established as an important mediator of tumor-stromal interaction during cancer metastasis. Imaging the in vivo dynamic of TGFβ signaling activity during cancer metastasis is critical for understanding the pathogenesis of the disease, and for the development of effective anti-metastasis treatments. In this chapter, I describe several xenograft methods to introduce human breast cancer cells into nude mice in order to generate spontaneous and experimental metastases, as well as the luciferase-based bioluminescence imaging method for quantitative imaging analysis of TGFβ signaling in tumor cells during metastasis.

  8. Gastric Metastasis of Breast Cancer: A Case Series

    PubMed Central

    dos Santos Fernandes, Gustavo; Batista Bugiato Faria, Luiza D.; de Assis Pereira, Isadora; Neves, Natália C. Moreira; Vieira, Yasmine Oliveira; Leal, Alessandro I. Cavalcanti

    2016-01-01

    Gastric metastasis is rare but it can be the initial symptom of cancer. The second leading cause of this type of metastasis is breast cancer. A lack of clinical signs and nonspecific side effects of the treatment of primary tumors can lead to the misdiagnosis of metastatic gastric cancer. Upper gastrointestinal endoscopy with biopsy and immunohistochemistry should be used for diagnosis. Treatment is palliative; it includes chemo, endocrine, and radiation therapies. Four patients with breast cancer and gastric metastasis were identified. All the patients tested positive for estrogen and progesterone receptors, and received chemotherapy and hormone therapy. One patient underwent surgery and two received radiation therapy. Patients with breast cancer and gastrointestinal symptoms should be investigated for gastric metastasis, given its morbidity and negative impact on quality of life. PMID:27746881

  9. Solitary Spinal Epidural Metastasis from Prostatic Small Cell Carcinoma

    PubMed Central

    Maeng, Young Hee

    2016-01-01

    Solitary, spinal epidural metastasis (SEM) that is not related to vertebral metastasis is very rare. And solitary SEM from prostatic cancer is rarely found in previously published reports. However, it is clinically significant due to the possibility of neurologic dysfunction, and it can be assessed by MRI. In this report, we show a case of solitary SEM arising from prostatic small cell carcinoma detected by MRI. PMID:27413569

  10. An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis.

    PubMed

    Paschall, Amy V; Liu, Kebin

    2016-01-01

    Metastasis is the primary cause of mortality of breast cancer patients. The mechanism underlying cancer cell metastasis, including breast cancer metastasis, is largely unknown and is a focus in cancer research. Various breast cancer spontaneous metastasis mouse models have been established. Here, we report a simplified procedure to establish orthotopic transplanted breast cancer primary tumor and resultant spontaneous metastasis that mimic human breast cancer metastasis. Combined with the bioluminescence live tumor imaging, this mouse model allows tumor growth and progression kinetics to be monitored and quantified. In this model, a low dose (1 x 10(4) cells) of 4T1-Luc breast cancer cells was injected into BALB/c mouse mammary fat pad using a tuberculin syringe. Mice were injected with luciferin and imaged at various time points using a bioluminescent imaging system. When the primary tumors grew to the size limit as in the IACUC-approved protocol (approximately 30 days), mice were anesthetized under constant flow of 2% isoflurane and oxygen. The tumor area was sterilized with 70% ethanol. The mouse skin around the tumor was excised to expose the tumor which was removed with a pair of sterile scissors. Removal of the primary tumor extends the survival of the 4T-1 tumor-bearing mice for one month. The mice were then repeatedly imaged for metastatic tumor spreading to distant organs. Therapeutic agents can be administered to suppress tumor metastasis at this point. This model is simple and yet sensitive in quantifying breast cancer cell growth in the primary site and progression kinetics to distant organs, and thus is an excellent model for studying breast cancer growth and progression, and for testing anti-metastasis therapeutic and immunotherapeutic agents in vivo. PMID:27584043

  11. ["Clown nose"--skin metastasis of breast cancer].

    PubMed

    Soyer, H P; Cerroni, L; Smolle, J; Kerl, H

    1990-10-01

    We report on a 74-year-old woman showing a reddish infiltration of the tip of the nose, which had appeared 3 months ago. Clinically, we considered the following differential diagnoses: sarcoidosis, rosacea, pseudolymphoma, and metastasis. Histological and immunohistological investigation proved a cutaneous metastasis of carcinoma of the breast. Our case report gives evidence of the fact that cutaneous metastases of systemic malignancies are frequently located in acral regions of the skin. PMID:2291293

  12. Brain metastasis from ovarian cancer: a systematic review.

    PubMed

    Pakneshan, Shabnam; Safarpour, Damoun; Tavassoli, Fattaneh; Jabbari, Bahman

    2014-08-01

    To review the existing literature on brain metastasis (BM) from ovarian cancer and to assess the frequency, anatomical, clinical and paraclinical information and factors associated with prognosis. Ovarian cancer is a rare cause of brain metastasis with a recently reported increasing prevalence. Progressive neurologic disability and poor prognosis is common. A comprehensive review on this subject has not been published previously. This systematic literature search used the Pubmed and Yale library. A total of 66 publications were found, 57 of which were used representing 591 patients with BM from ovarian cancer. The median age of the patients was 54.3 years (range 20-81). A majority of patients (57.3 %) had multiple brain lesions. The location of the lesion was cerebellar (30 %), frontal (20 %), parietal (18 %) and occipital (11 %). Extracranial metastasis was present in 49.8 % of cases involving liver (20.7 %), lung (20.4 %), lymph nodes (12.6 %), bones (6.6 %) and pelvic organs (4.3 %). The most common symptoms were weakness (16 %), seizures (11 %), altered mentality (11 %) visual disturbances (9 %) and dizziness (8 %). The interval from diagnosis of breast cancer to BM ranged from 0 to 133 months (median 24 months) and median survival was 8.2 months. Local radiation, surgical resection, stereotactic radiosurgery and medical therapy were used. Factors that significantly increased the survival were younger age at the time of ovarian cancer diagnosis and brain metastasis diagnosis, lower grade of the primary tumor, higher KPS score and multimodality treatment for the brain metastases. Ovarian cancer is a rare cause of brain metastasis. Development of brain metastasis among older patients and lower KPS score correlate with less favorable prognosis. The more prolonged survival after using multimodality treatment for brain metastasis is important due to potential impact on management of brain metastasis in future.

  13. ["Clown nose"--skin metastasis of breast cancer].

    PubMed

    Soyer, H P; Cerroni, L; Smolle, J; Kerl, H

    1990-10-01

    We report on a 74-year-old woman showing a reddish infiltration of the tip of the nose, which had appeared 3 months ago. Clinically, we considered the following differential diagnoses: sarcoidosis, rosacea, pseudolymphoma, and metastasis. Histological and immunohistological investigation proved a cutaneous metastasis of carcinoma of the breast. Our case report gives evidence of the fact that cutaneous metastases of systemic malignancies are frequently located in acral regions of the skin.

  14. [Jawbone metastasis masquerading as dental pain].

    PubMed

    Goldman, Y; Yarom, N

    2016-01-01

    Metastases to the oral cavity are rare. However, in 25% of cases, oral symptoms will be the first sign of metastatic disease. The incidence of jaws metastases is twice as high as the incidence of metastases to the soft tissues of the oral cavity. In some cases, jaws metastases can mimic dental or periodontal pain. We report a case of a 67 year old female who was referred to our clinic because of severe pain on her left posterior mandible which was not relieved by endodontic treatment of the first and second molar. She was diagnosed with breast cancer in 2005 and had been treated with surgery, chemotherapy and radiotherapy. Seven years later, lung metastases were found and she was treated with chemotherapy. Later on, brain metastases developed which had been treated with radiotherapy. On presentation, she complained of pain on the posterior left mandible which was accompanied by a burning sensation of the lower left lip and chin. CT scan revealed a soft tissue mass perforating the lingual and buccal plates of the posterior left mandible, which was compatible with a diagnosis of metastasis. Radiotherapy rapidly relieved the pain. Unfortunately, the patient passed away one month later. Dentists should be able to recognize the signs and symptoms associated with metastases to the jaws and should include it in the differential diagnosis, especially in patients with oncologic background. PMID:27295929

  15. Skeletal metastasis: the effect on immature skeleton

    SciTech Connect

    Ogden, J.A.; Ogden, D.A.

    1982-12-01

    The unique opportunity to study the entire appendicular skeleton of a child who died from metastatic angiosarcoma allowed detailed assessment of radiographically evident involvement. Virtually every portion of the appendicular skeleton had evidence of metastatic disease. However, the extent of involvement was extremely variable, especially when contralateral regions were assessed. The most likely region of metastasis, the metaphysis, is normally a fenestrated cortex of woven bone in the young child, rather than a well demarcated cortex formed by osteon (lamellar) bone, as it is in the adult. The pattern of destruction is such that less extensive areas may be involved before becoming radiographically evident, and trabecular bone involvement may be evident even without cortical damage. The metaphyseal metastatic spread supports the concept of arterial hematogeneous dissemination, comparable to osteomyelitis in the child. Pathologic metaphyseal fractures involved both proximal humeri; the fracture also extended along a portion of the methaphyseal-physeal interface in one humerus. In one distal femur the physis readily separated from the metaphysis; this was a nondisplaced type 1 growth mechanism injury.

  16. Odontogenic ghost cell carcinoma with pulmonary metastasis

    PubMed Central

    Sukumaran, Renu; Somanathan, Thara; Kattoor, Jayasree

    2015-01-01

    Odontogenic ghost cell carcinoma (OGCC) is an exceptionally rare malignant odontogenic epithelial tumor. It is characterized by ameloblastic-like islands of epithelial cells with aberrant keratinization in the form of ghost cells with varying amounts of dysplastic dentin. Malignant histological characteristics include infiltration, cellular pleomorphism, numerous mitosis and necrosis. Its biological behavior varies from slow-growing locally invasive lesions to rapidly growing highly aggressive tumors. OGCC metastasizing to distant sites is extremely rare. Only three cases of metastasis have been reported in literature. We are reporting the case of a 54-year-old male patient who presented with tender swelling in the malar region. Histopathological examination revealed OGCC and he received postoperative radiotherapy. Two years later, he presented with a lung mass. Biopsy from the lung lesion showed the same morphology as that of maxillary tumor with scattered ghost cells. This case points to the aggressive behavior of OGCC and its metastatic potential. It also highlights the need for long-term follow-up of these patients. PMID:26980967

  17. Preferentially Expressed Antigen of Melanoma Prevents Lung Cancer Metastasis

    PubMed Central

    Sun, Zhengwang; Li, Lei; Lin, Zaijun; Xu, Wei; Han, Shuai; Cao, Wenjiao; Xu, Yunfei; Song, Dianwen; Yang, Xinghai; Xiao, Jianru

    2016-01-01

    Lung cancer is the most common cause of cancer death worldwide. The poor survival rate is largely due to the extensive local invasion and metastasis. However, the mechanisms underlying the invasion and metastasis of lung cancer cells remain largely elusive. In this study, we examined the role of preferentially expressed antigen of melanoma (PRAME) in lung cancer metastasis. Our results show that PRAME is downregulated in lung adenocarcinoma and lung bone metastasis compared with normal human lung. Knockdown of PRAME decreases the expression of E-Cadherin and promotes the proliferation, invasion, and metastasis of lung cancer cells by regulating multiple critical genes, most of which are related to cell migration, including MMP1, CCL2, CTGF, and PLAU. Clinical data analysis reveals that the expression of MMP1 correlates with the clinical features and outcome of lung adenocarcinoma. Taken together, our data demonstrate that PRAME plays a role in preventing the invasion and metastasis of lung adenocarcinoma and novel diagnostic or therapeutic strategies can be developed by targeting PRAME. PMID:27391090

  18. Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis.

    PubMed

    You, Yiwen; Shan, Ying; Chen, Jing; Yue, Huijun; You, Bo; Shi, Si; Li, Xingyu; Cao, Xiaolei

    2015-12-01

    Nasopharyngeal cancer (NPC) is an endemic type of head and neck cancer with a high rate of cervical lymph node metastasis. Metastasis is the major cause of death in NPC patients. Increasing evidence indicates that exosomes play a pivotal role in promoting cancer metastasis by enhancing angiogenesis and ECM degradation. Matrix metalloproteinase 13 is an important kind of matrix proteinase that is often overexpressed in various tumors and increases the risk of metastasis. However, little is known about the potential role of MMP13-containing exosomes in NPC. In this study, we found that MMP13 was overexpressed in NPC cells and exosomes purified from conditioned medium (CM) as well as NPC patients' plasma. Transwell analysis revealed that MMP13-containing exosomes facilitated the metastasis of NPC cells. Furthermore, siRNA inhibited the effect of MMP13-containing exosomes on tumor cells metastasis as well as angiogenesis. The current findings provided novel insight into the vital role of MMP13-containing exosomes in NPC progression which might offer unique insights for potential therapeutic strategies for NPC progressions. PMID:26362844

  19. Severe pulmonary metastasis in obese and diabetic mice.

    PubMed

    Mori, Akinori; Sakurai, Hiroaki; Choo, Min-Kyung; Obi, Ryosuke; Koizumi, Keiichi; Yoshida, Chiho; Shimada, Yutaka; Saiki, Ikuo

    2006-12-15

    Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis. PMID:16998795

  20. Effects of vascular targeting photodynamic therapy on lymphatic tumor metastasis

    NASA Astrophysics Data System (ADS)

    Fateye, B.; He, C.; Chen, B.

    2009-06-01

    Vascular targeting photodynamic therapy (vPDT) is currently in clinical trial for prostate cancer (PCa) treatment. In order to study the effect of vPDT on tumor metastasis, GFP-PC3 or PC-3 xenografts were treated with verteporfin (BPD) PDT. Vascular function was assessed by ultrasound imaging; lymph node and lung metastasis were assessed by fluorescence imaging. vPDT significantly reduced tumor blood flow within 30minutes to 2 hours of treatment. Sub-curative treatment resulted in re-perfusion within 2 weeks of treatment and increased lymph node metastasis. With curative doses, no metastasis was observed. In order to identify cellular or matrix factors and cytokines implicated, conditioned medium from BPD PDTtreated endothelial cells was incubated with PC3 cells in vitro. Tumor cell proliferation and migration was assessed. By immunoblotting, we evaluated the change in mediators of intracellular signaling or that may determine changes in tumor phenotype. Low sub-curative dose (200ng/ml BPD) of endothelial cells was associated with ~15% greater migration in PC3 cells when compared with control. This dose was also associated with sustained activation of Akt at Ser 473, an upstream effector in the Akt/ mTOR pathway that has been correlated with Gleason scores in PCa and with survival and metastasis in vitro and in vivo. In conclusion, the study implicates efficacy of PDT of endothelial cells as an important determinant of its consequences on adjacent tumor proliferation and metastasis.

  1. Dequalinium blocks macrophage-induced metastasis following local radiation.

    PubMed

    Timaner, Michael; Bril, Rotem; Kaidar-Person, Orit; Rachman-Tzemah, Chen; Alishekevitz, Dror; Kotsofruk, Ruslana; Miller, Valeria; Nevelsky, Alexander; Daniel, Shahar; Raviv, Ziv; Rotenberg, Susan A; Shaked, Yuval

    2015-09-29

    A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis. PMID:26348470

  2. Dequalinium blocks macrophage-induced metastasis following local radiation

    PubMed Central

    Kaidar-Person, Orit; Rachman-Tzemah, Chen; Alishekevitz, Dror; Kotsofruk, Ruslana; Miller, Valeria; Nevelsky, Alexander; Daniel, Shahar; Raviv, Ziv; Rotenberg, Susan A.; Shaked, Yuval

    2015-01-01

    A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis. PMID:26348470

  3. Emerging molecular basis of hematogenous metastasis in gastric cancer

    PubMed Central

    Zhong, Jing; Chen, Yan; Wang, Liang-Jing

    2016-01-01

    Lymphatic metastasis is commonly observed in gastric cancer (GC), but hematogenous metastasis is more likely responsible for the cancer-related mortality. Since Stephen Paget first introduced the “seed and soil hypothesis” a century ago, growing evidence recognizes that numerous essential secreted factors and signaling pathway effectors participate in the pre-metastatic niche formation and distant organ metastasis. The cross-talk between GC cells and surrounding microenvironment may consist of a series of interrelated steps, including epithelial mesenchymal transition, intravasation into blood vessels, circulating tumor cell translocation, and secondary organ metastasis. Secreted factors including vascular endothelial growth factor (VEGF), matrix metalloproteinases and cancer-derived extracellular vesicles, especially exosomes, are essential in formation of premetastatic niche. Circulating tumor cells and microRNAs represent as ‘‘metastatic intermediates’’ between primary tumors and sites of dissemination. Many biomarkers have been identified as novel metastatic markers and prognostic effectors. In addition, molecular therapy has been designed to target biomarkers such as growth factors (human epidermal growth factor receptor 2, VEGF) and chemokines, although they have not clearly proven to be effective in inhibiting GC metastasis in clinical trials. In this review, we will systematically discuss the emerging molecules and their microenvironment in hematogenous metastasis of GC, which may help us to find new therapeutic strategies in the future. PMID:26937132

  4. FRZB up-regulated in hepatocellular carcinoma bone metastasis

    PubMed Central

    Huang, Jia; Hu, Wenhao; Lin, Xiangjin; Wang, Xuanwei; Jin, Ketao

    2015-01-01

    The clinical relevance of frizzled-related protein (FRZB) in hepatocellular carcinoma (HCC) bone metastasis remains uncertain. The aim of this study was to assess the clinical relationship of FRZB in patients with HCC bone metastasis after surgical resection. FRZB expression was evaluated by immunohistochemistry in formalin-fixed paraffin embedded (FFPE) HCC and paired bone metastasis tissues from 13 patients that underwent surgical resection. The clinical characteristics of 13 HCC patients with synchronous or metachronous bone metastasis received surgery were retrospectively reviewed. We found that FRZB was positive in 9 HCC tissues (69.2%) and in 11 paired bone metastatic tissues (84.6%) among these 13 paired samples. The expression of FRZB in the bone metastases was noticeably higher than that in the paired HCC tissues. The expression of FRZB was up-regulated in 10 (76.9%) paired bone metastases tissues. FRZB expression was up-regulated in HCC bone metastasis tissue, which suggested that FRZB might play a key role in the HCC bone metastasis. PMID:26722540

  5. Remodeling of the Methylation Landscape in Breast Cancer Metastasis

    PubMed Central

    Reyngold, Marsha; Turcan, Sevin; Giri, Dilip; Kannan, Kasthuri; Walsh, Logan A.; Viale, Agnes; Drobnjak, Marija; Vahdat, Linda T.; Lee, William; Chan, Timothy A.

    2014-01-01

    The development of breast cancer metastasis is accompanied by dynamic transcriptome changes and dramatic alterations in nuclear and chromatin structure. The basis of these changes is incompletely understood. The DNA methylome of primary breast cancers contribute to transcriptomic heterogeneity and different metastatic behavior. Therefore we sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome and transcriptome of 44 matched primary breast tumors and regional metastases. Striking subtype-specific patterns of metastasis-associated methylome remodeling were observed, which reflected the molecular heterogeneity of breast cancers. These divergent changes occurred primarily in CpG island (CGI)-poor areas. Regions of methylome reorganization shared by the subtypes were also observed, and we were able to identify a metastasis-specific methylation signature that was present across the breast cancer subclasses. These alterations also occurred outside of CGIs and promoters, including sequences flanking CGIs and intergenic sequences. Integrated analysis of methylation and gene expression identified genes whose expression correlated with metastasis-specific methylation. Together, these findings significantly enhance our understanding of the epigenetic reorganization that occurs during regional breast cancer metastasis across the major breast cancer subtypes and reveal the nature of methylome remodeling during this process. PMID:25083786

  6. Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis.

    PubMed

    You, Yiwen; Shan, Ying; Chen, Jing; Yue, Huijun; You, Bo; Shi, Si; Li, Xingyu; Cao, Xiaolei

    2015-12-01

    Nasopharyngeal cancer (NPC) is an endemic type of head and neck cancer with a high rate of cervical lymph node metastasis. Metastasis is the major cause of death in NPC patients. Increasing evidence indicates that exosomes play a pivotal role in promoting cancer metastasis by enhancing angiogenesis and ECM degradation. Matrix metalloproteinase 13 is an important kind of matrix proteinase that is often overexpressed in various tumors and increases the risk of metastasis. However, little is known about the potential role of MMP13-containing exosomes in NPC. In this study, we found that MMP13 was overexpressed in NPC cells and exosomes purified from conditioned medium (CM) as well as NPC patients' plasma. Transwell analysis revealed that MMP13-containing exosomes facilitated the metastasis of NPC cells. Furthermore, siRNA inhibited the effect of MMP13-containing exosomes on tumor cells metastasis as well as angiogenesis. The current findings provided novel insight into the vital role of MMP13-containing exosomes in NPC progression which might offer unique insights for potential therapeutic strategies for NPC progressions.

  7. AACR Centennial Series: The Biology of Cancer Metastasis: Historical Perspective

    PubMed Central

    Talmadge, James E; Fidler, Isaiah J

    2014-01-01

    Metastases resistant to therapy is the major cause of death from cancer. Despite almost 200 years of study, the process of tumor metastasis remains controversial. Stephen Paget initially identified the role of host-tumor interactions on the basis of a review of autopsy records. His “seed and soil” hypothesis was substantiated a century later with experimental studies and numerous reports have confirmed these seminal observations. Inarguably, an improved understanding of the metastatic process and the attributes of the cells selected by this process are critical to the treatment of patients with systemic disease. In many patients, metastasis has occurred by the time of diagnosis, such that metastasis prevention may not be relevant, and treatment of systemic disease, as well as the identity of patients with early disease, should be our goal. During the last three decades, revitalized research has focused on new discoveries in the biology of metastasis. While our understanding of the molecular events that regulate metastasis has improved; nonetheless, the relevant contributions and timing of molecular lesion(s) potentially involved in its pathogenesis remain unclear. The history of pioneering observations and discussion of current controversies should help investigators understand the complex and multifactorial interactions between the host and selected tumor cells that contribute to fatal metastasis and allow for the design of successful therapy. PMID:20610625

  8. Cellular and molecular processes in ovarian cancer metastasis. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis.

    PubMed

    Yeung, Tsz-Lun; Leung, Cecilia S; Yip, Kay-Pong; Au Yeung, Chi Lam; Wong, Stephen T C; Mok, Samuel C

    2015-10-01

    Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-yr survival rate of <30%. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Owing to a substantially lower survival rate at late stages of disease than at earlier stages, the major cause of ovarian cancer deaths is believed to be therapy-resistant metastasis. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and the importance of the "seed-and-soil" hypothesis for ovarian cancer metastasis. In this review we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease.

  9. Prognostic Factors After Extraneural Metastasis of Medulloblastoma

    SciTech Connect

    Mazloom, Ali; Zangeneh, Azy H.; Paulino, Arnold C.

    2010-09-01

    Purpose: To review the existing literature regarding the characteristics, prognostic factors, treatment, and survival of patients with medulloblastoma, who develop extraneural metastasis (ENM). Methods and Materials: A PubMed search of English language articles from 1961 to 2007 was performed, yielding 47 articles reporting on 119 patients. Factors analyzed included age, time interval to development of ENM, ENM location, central nervous system (CNS) involvement, treatment, and outcome. Results: Sites of ENM included bone in 84% of patients, bone marrow in 27% of patients, lymph nodes in 15% of patients, lung in 6% of patients, and liver in 6% of patients. Median survival was 8 months after diagnosis of ENM. The 1-, 2-, and 5-year overall survival (OS) rates after diagnosis of ENM were 41.9%, 31.0%, and 26.0%, respectively. The 1-, 2-, and 5-year progression-free survival (PFS) rates after diagnosis of ENM were 34.5%, 23.2%, and 13.4%, respectively. For patients without CNS involvement at the time of ENM diagnosis, the 1-, 2-, and 5-year OS rates for those treated with and without radiotherapy (RT) were 82.4%, 64.8%, and 64.8% vs. 51.0%, 36.6%, and 30.5%, respectively (p = 0.03, log-rank test). RT did not significantly improve OS or PFS rates for those with CNS involvement. Concurrent CNS involvement, ENM in the lung or liver, a time interval of <18 months to development of ENM, and a patient age of <16 years at ENM diagnosis were found to be negative prognostic factors for both OS and PFS. Conclusions: Several prognostic factors were identified for patients with ENM from medulloblastoma. Patients without concurrent CNS involvement, who received RT after ENM diagnosis had an OS and PFS benefit compared to those who did not receive RT.

  10. Liver Metastasis of Gastrointestinal Neuroendocrine Tumors: A Single Center Experience

    PubMed Central

    Geramizadeh, Bita; Kashkooe, Ali; Malekhosseini, Seyed Ali

    2016-01-01

    Background Gastrointestinal neuroendocrine tumors (GI-NETs) are potentially malignant tumors, and their most common location of metastasis is the liver. Objectives In this report, we will describe our experience with some clinical and pathologic findings of hepatic metastasis in a group of cases of GI-NETs at the largest referral center of GI and liver diseases in south Iran. Materials and Methods In this four-year study (2011 - 2014), all GI and liver NETs were extracted from the pathology files of hospitals affiliated with Shiraz University of Medical Sciences. After classification based on the world health organization guidelines, the patients were evaluated according to their location, sex, age, and proliferative index. After studying the imaging and clinical charts of liver-NET cases with an unknown primary location, a complete panel of immunohistochemical markers (TTF-1, CDX-2, CK-7, CK-2, etc.) was used to find the primary GI location. Carcinoid tumors from other sites, such as the lung, were omitted from this study. Results The most common primary site of metastatic GI-NET to the liver in our center was the small intestine, which was also the most frequent location of GI-NET without liver metastasis. No cases of appendiceal-NET were found with liver metastasis. In 8 cases (11.6%) with liver-NETs, no primary location was identified. GI-NETs with liver metastasis had a significantly higher grade and proliferative index compared with NETs without liver metastasis. Conclusions Liver metastasis of neuroendocrine tumors in Iran presents in a very similar manner as that seen in western countries. In about 89% of cases with liver-NET, complete imaging, clinical, and pathological studies can help to identify the primary origin of the liver-NET, which is very important in the patient’s management. PMID:27330538

  11. Targeting type Iγ phosphatidylinositol phosphate kinase inhibits breast cancer metastasis.

    PubMed

    Chen, C; Wang, X; Xiong, X; Liu, Q; Huang, Y; Xu, Q; Hu, J; Ge, G; Ling, K

    2015-08-27

    Most deaths from breast cancer are caused by metastasis, a complex behavior of cancer cells involving migration, invasion, survival and microenvironment manipulation. Type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) regulates focal adhesion assembly and its phosphorylation at Y639 is critical for cell migration induced by EGF. However, the role of this lipid kinase in tumor metastasis remains unclear. Here we report that PIPKIγ is vital for breast cancer metastasis. Y639 of PIPKIγ can be phosphorylated by stimulation of EGF and hepatocyte growth factor (HGF), two promoting factors for breast cancer progression. Histological analysis revealed elevated Y639 phosphorylation of PIPKIγ in invasive ductal carcinoma lesions and suggested a positive correlation with tumor grade. Orthotopically transplanted PIPKIγ-depleted breast cancer cells showed substantially reduced growth and metastasis, as well as suppressed expression of multiple genes related to cell migration and microenvironment manipulation. Re-expression of wild-type PIPKIγ in PIPKIγ-depleted cells restored tumor growth and metastasis, reinforcing the importance of PIPKIγ in breast cancer progression. Y639-to-F or a kinase-dead mutant of PIPKIγ could not recover the diminished metastasis in PIPKIγ-depleted cancer cells, suggesting that Y639 phosphorylation and lipid kinase activity are both required for development of metastasis. Further analysis with in vitro assays indicated that depleting PIPKIγ inhibited cell proliferation, MMP9 secretion and cell migration and invasion, lending molecular mechanisms for the eliminated cancer progression. These results suggest that PIPKIγ, downstream of EGF and/or HGF receptor, participates in breast cancer progression from multiple aspects and deserves further studies to explore its potential as a therapeutic target.

  12. Colony-stimulating factor 1 potentiates lung cancer bone metastasis.

    PubMed

    Hung, Jaclyn Y; Horn, Diane; Woodruff, Kathleen; Prihoda, Thomas; LeSaux, Claude; Peters, Jay; Tio, Fermin; Abboud-Werner, Sherry L

    2014-04-01

    Colony-stimulating factor 1 (CSF1) is essential for osteoclastogenesis that mediates osteolysis in metastatic tumors. Patients with lung cancer have increased CSF1 in serum and high levels are associated with poor survival. Adenocarcinomas metastasize rapidly and many patients suffer from bone metastasis. Lung cancer stem-like cells sustain tumor growth and potentiate metastasis. The purpose of this study was to determine the role of CSF1 in lung cancer bone metastasis and whether inhibition of CSF1 ameliorates the disease. Human lung adenocarcinoma A549 cells were examined in vitro for CSF1/CSF1R. A549-luc cells were injected intracardiac in NOD/SCID mice and metastasis was assessed. To determine the effect of CSF1 knockdown (KD) in A549 cells on bone metastasis, cells were stably transfected with a retroviral vector containing short-hairpin CSF1 (KD) or empty vector (CT). Results showed that A549 cells express CSF1/CSF1R; CSF1 increased their proliferation and invasion, whereas soluble CSF1R inhibited invasion. Mice injected with A549-luc cells showed osteolytic bone lesions 3.5 weeks after injection and lesions increased over 5 weeks. Tumors recapitulated adenocarcinoma morphology and showed osteoclasts along the tumor/bone interface, trabecular, and cortical bone loss. Analyses of KD cells showed decreased CSF1 protein levels, reduced colony formation in soft agar assay, and decreased fraction of stem-like cells. In CSF1KD mice, the incidence of tumor metastasis was similar to controls, although fewer CSF1KD mice had metastasis in both hind limbs. KD tumors showed reduced CSF1 expression, Ki-67+ cells, and osteoclasts. Importantly, there was a low incidence of large tumors >0.1 mm(2) in CSF1KD mice compared with control mice (10% vs 62.5%). This study established a lung osteolytic bone metastasis model that resembles human disease and suggests that CSF1 is a key determinant of cancer stem cell survival and tumor growth. Results may lead to novel strategies to

  13. N-glycans and metastasis in galectin-3 transgenic mice.

    PubMed

    More, Shyam K; Srinivasan, Nithya; Budnar, Srikanth; Bane, Sanjay M; Upadhya, Archana; Thorat, Rahul A; Ingle, Arvind D; Chiplunkar, Shubhada V; Kalraiya, Rajiv D

    2015-05-01

    Poly-N-acetyl-lactosamine (polyLacNAc) on N-glycans facilitate lung specific metastasis of melanoma cells by serving as high affinity ligands for galectin-3, expressed in highest amounts in the lungs, on almost all its tissue compartments including on the surface of vascular endothelium. PolyLacNAc not only aids in initial arrest on the organ endothelium but in all the events of extravasation. Inhibition of polyLacNAc synthesis, or competitive inhibition of its interaction with galectin-3 all inhibited these processes and experimental metastasis. Transgenic galectin-3 mice, viz., gal-3(+/+) (wild type), gal-3(+/-) (hemizygous) and gal-3(-/-) (null) have been used to prove that galectin-3/polyLacNAc interactions are indeed critical for lung specific metastasis. Gal-3(+/-) mice which showed <50% expression of galectin-3 on the lungs also showed proportionate decrease in the number of B16F10 melanoma metastatic colonies affirming that galectin-3 and polyLacNAc interactions are indeed key determinants of lung metastasis. However, surprisingly, the number and size of metastatic colonies in gal-3(-/-) mice was very similar as that seen in gal-3(+/+) mice. The levels of lactose binding lectins on the lungs and the transcripts of other galectins (galectin-1, -8 and -9) which are expressed on lungs and have similar sugar binding specificities as galectins-3, remain unchanged in gal-3(+/+) and gal-3(-/-) mice. Further, inhibition of N-glycosylation with Swainsonine (SW) which drastically reduces metastasis of B16F10 cells in gal-3(+/+) mice, did not affect lung metastasis when assessed in gal-3(-/-) mice. Together, these results rule out the possibility of some other galectin taking over the function of galectin-3 in gal-3(-/-) mice. Chimeric mice generated to assess if absence of any effect on metastasis is due to compromised tumor immunity by replacing bone marrow of gal-3(-/-) mice with that from gal-3(+/+) mice, also failed to impact melanoma metastasis. As galectin-3

  14. The molecular signature of breast cancer metastasis to bone.

    PubMed

    Bahrami, Tayyeb; Mokmeli, Sharareh; Hossieni, Hossien; Pourpaknia, Reza; Makani, Zahra; Salmaninejad, Arash; Estiar, Mehrdad A; Hossieni, Ali; Farshbaf, Alieh

    2016-10-01

    Distant metastasis during the advanced stage of malignant tumor progression can cause considerable morbidity in cancer patients. Bone is known to be one of the most common sites of distant metastasis in patients with breast cancer (BC). BC metastases in bone are associated with excessive skeletal complications. These complications can be fatal and reduce quality of life of patients. It is important to understand the metastatic process of BC to bone to improve quality of life and design new therapeutic methods. At present, the molecular mechanisms leading to the BC metastasis to bone are not fully understood. Studying the molecular basis of BC metastasis to bone might improve our insight into this complex process. In addition, it can provide novel approaches for designing advanced and effective targeted therapies. The present article aimed to review the published papers on the molecular basis of the metastatic process of BC to bone, focusing on involved genes and signaling networks. Furthermore, we propose potential therapeutic targets that may be more effective for the inhibition and treatment of BC metastasis to bone. PMID:27384592

  15. Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion

    PubMed Central

    Kenny, Hilary A.; Chiang, Chun-Yi; White, Erin A.; Schryver, Elizabeth M.; Habis, Mohammed; Romero, Iris L.; Ladanyi, Andras; Penicka, Carla V.; George, Joshy; Matlin, Karl; Montag, Anthony; Wroblewski, Kristen; Yamada, S. Diane; Mazar, Andrew P.; Bowtell, David; Lengyel, Ernst

    2014-01-01

    Ovarian cancer (OvCa) metastasizes to organs in the abdominal cavity, such as the omentum, which are covered by a single layer of mesothelial cells. Mesothelial cells are generally thought to be “bystanders” to the metastatic process and simply displaced by OvCa cells to access the submesothelial extracellular matrix. Here, using organotypic 3D cultures, we found that primary human mesothelial cells secrete fibronectin in the presence of OvCa cells. Moreover, we evaluated the tumor stroma of 108 human omental metastases and determined that fibronectin was consistently overexpressed in these patients. Blocking fibronectin production in primary mesothelial cells in vitro or in murine models, either genetically (fibronectin 1 floxed mouse model) or via siRNA, decreased adhesion, invasion, proliferation, and metastasis of OvCa cells. Using a coculture model, we determined that OvCa cells secrete TGF-β1, which in turn activates a TGF-β receptor/RAC1/SMAD-dependent signaling pathway in the mesothelial cells that promotes a mesenchymal phenotype and transcriptional upregulation of fibronectin. Additionally, blocking α5 or β1 integrin function with antibodies reduced metastasis in an orthotopic preclinical model of OvCa metastasis. These findings indicate that cancer-associated mesothelial cells promote colonization during the initial steps of OvCa metastasis and suggest that mesothelial cells actively contribute to metastasis. PMID:25202979

  16. Quantitation of Intra-peritoneal Ovarian Cancer Metastasis.

    PubMed

    Lewellen, Kyle A; Metzinger, Matthew N; Liu, Yueying; Stack, M Sharon

    2016-01-01

    Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. Mortality is due to diagnosis of 75% of women with late stage disease, when metastasis is already present. EOC is characterized by diffuse and widely disseminated intra-peritoneal metastasis. Cells shed from the primary tumor anchor in the mesothelium that lines the peritoneal cavity as well as in the omentum, resulting in multi-focal metastasis, often in the presence of peritoneal ascites. Efforts in our laboratory are directed at a more detailed understanding of factors that regulate EOC metastatic success. However, quantifying metastatic tumor burden represents a significant technical challenge due to the large number, small size and broad distribution of lesions throughout the peritoneum. Herein we describe a method for analysis of EOC metastasis using cells labeled with red fluorescent protein (RFP) coupled with in vivo multispectral imaging. Following intra-peritoneal injection of RFP-labelled tumor cells, mice are imaged weekly until time of sacrifice. At this time, the peritoneal cavity is surgically exposed and organs are imaged in situ. Dissected organs are then placed on a labeled transparent template and imaged ex vivo. Removal of tissue auto-fluorescence during image processing using multispectral unmixing enables accurate quantitation of relative tumor burden. This method has utility in a variety of applications including therapeutic studies to evaluate compounds that may inhibit metastasis and thereby improve overall survival. PMID:27500635

  17. Dietary linoleate-enhanced metastasis of 4526 murine mammary tumors

    SciTech Connect

    Hubbard, N.E.

    1987-01-01

    The influence of quantitative differences in dietary linoleic acid (18:2) and of the cyclooxygenase inhibitor, indomethacin (IM), on the metastasis of line 4526 mammary tumors was investigated. All mice were fed high fat (20%, w/w), semipurified diets that were prepared using different mixtures of coconut (primarily saturated) and safflower (mostly 18:2) oil and thus contained either 1, 2, 4, 8, or 12% 18:2 (w/w). The spontaneous metastasis of 4526 tumor cells from primary sites, was increased 2-4 fold in mice that were fed diets containing higher levels of 18:2 (8 and 12%). Chronic treatment of mice with a relatively low dosage of IM reduced the growth rate of primary 4526 tumors, slightly reduced metastasis in mice fed 1 and 4% 18:2, and completely inhibited the increased metastasis observed in mice fed 12% 18:2. Treatment with a higher dosage of IM reduced metastasis even further compared to controls, but did not decrease growth rate compared to the low dosage of IM. The level of 18:2 in the diet did not appear to affect the incorporation of {sup 3}H-thymidine into tumor cells of metastatic lung nodules. The effect of 18:2 may be through a modulation of arachidonic acid metabolism. This modulation, in turn, may affect particular steps in the metastatic cascade such as lodgement and survival of tumor cells.

  18. ZBTB7A suppresses melanoma metastasis by transcriptionally repressing MCAM

    PubMed Central

    Liu, Xue-Song; Genet, Matthew D; Haines, Jenna E; Mehanna, Elie K; Wu, Shaowei; Chen, Hung-I Harry; Chen, Yidong; Qureshi, Abrar A; Han, Jiali; Chen, Xiang; Fisher, David E; Pandolfi, Pier Paolo; Yuan, Zhi-Min

    2015-01-01

    The excessive metastatic propensity of melanoma makes it the most deadly form of skin cancer, yet the underlying mechanism of metastasis remains elusive. Here, mining of cancer genome datasets discovered a frequent loss of chromosome 19p13.3 and associated down-regulation of the zinc finger transcription factor ZBTB7A in metastatic melanoma. Functional assessment of ZBTB7A-regulated genes identified MCAM, which encodes an adhesion protein key to melanoma metastasis. Using an integrated approach, it is demonstrated that ZBTB7A directly binds to the promoter and transcriptionally represses the expression of MCAM, establishing ZBTB7A as a bona fide transcriptional repressor of MCAM. Consistently, down-regulation of ZBTB7A results in marked upregulation of MCAM and enhanced melanoma cell invasion and metastasis. An inverse correlation of ZBTB7A and MCAM expression in association with melanoma metastasis is further validated with data from analysis of human melanoma specimens. Implications Together these results uncover a previously unrecognized role of ZBTB7A in negative regulation of melanoma metastasis and have important clinical implications. PMID:25995384

  19. Biology of colorectal pulmonary metastasis: implications for surgical resection.

    PubMed

    Poullis, Michael; Littler, John; Gosney, John

    2012-02-01

    In colorectal cancer, little high grade evidence for cure, life extension, disease modification or palliation achieved by pulmonary metastasectomy exists. This has prompted the pulmonary metastasectomy in colorectal cancer (PulMiCC) trial. Reappraisal of the biological facts on colorectal metastasis may, however, shed light on an alternative avenue of clinical management. Early onset of metastasis, short doubling time and a short disease-free interval are all associated with poor clinical outcomes. Selecting who will be cured (i.e. no occult metastasis) remains the holy grail for pulmonary metastasectomy surgery. Serial CT scans can be utilized to calculate the tumour doubling time by volumetric analysis. Knowing the doubling time and size of the largest metastasis, which by definition is the first cell that has successfully spread from the primary site, the time of initial metastasis can be predicted. More importantly, using the doubling time, calculating the time interval from the primary surgery to the point at which all pulmonary metastases are visible should be possible. Perhaps watchful waiting, with interval CT scanning, followed by pulmonary metastasectomy should be utilized, rather than clinical opinion or randomization in a trial based upon first presentation. PMID:22159245

  20. Oxidative stress inhibits distant metastasis by human melanoma cells

    PubMed Central

    Piskounova, Elena; Agathocleous, Michalis; Murphy, Malea M.; Hu, Zeping; Huddlestun, Sara E.; Zhao, Zhiyu; Leitch, A. Marilyn; Johnson, Timothy M.; DeBerardinis, Ralph J.; Morrison, Sean J.

    2015-01-01

    Solid cancer cells commonly enter the blood and disseminate systemically but are highly inefficient at forming distant metastases for poorly understood reasons. We studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NSG mice. All melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficient metastasizers. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence upon NADPH-generating enzymes in the folate pathway. Anti-oxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo. PMID:26466563

  1. Matricellular proteins as regulators of cancer metastasis to bone.

    PubMed

    Trotter, Timothy N; Yang, Yang

    2016-01-01

    Metastasis is the major cause of death in cancer patients, and a frequent site of metastasis for many cancers is the bone marrow. Therefore, understanding the mechanisms underlying the metastatic process is necessary for future prevention and treatment. The tumor microenvironment is now known to play a role in the metastatic cascade, both at the primary tumor and in metastatic sites, and includes both cellular and non-cellular components. The extracellular matrix (ECM) provides structural support and signaling cues to cells. One particular group of molecules associated with the ECM, known as matricellular proteins, modulate multiple aspects of tumor biology, including growth, migration, invasion, angiogenesis and metastasis. These proteins are also important for normal function in the bone by regulating bone formation and bone resorption. Recent studies have described a link between some of these proteins and metastasis of various tumors to the bone. The aim of this review is to summarize what is currently known about matricellular protein influence on bone metastasis. Particular attention to the contribution of both tumor cells and non-malignant cells in the bone has been given.

  2. Contralateral axillary node metastasis from recurrence after conservative breast cancer surgery.

    PubMed

    Nishimura, Satoko; Koizumi, Mitsuru; Kawakami, Junko; Koyama, Masamichi

    2014-02-01

    Sentinel lymph node detection (SLND) with radiocolloid has become widely used for evaluation of nodal metastasis in primary breast cancer. However, the procedure for recurrent breast cancer is not well established. Contralateral axillary node metastasis is uncommon. We report 2 cases of contralateral axillary node metastasis with recurrent breast cancer. In the first case, contralateral node metastasis was found by SLND. In the other case without SLND, contralateral node metastasis developed after resection of local recurrence. FDG-avid contralateral node was pathologically diagnosed as metastasis. The SLND might be useful in patients with local recurrence after conservative breast cancer surgery. PMID:24368539

  3. Nanostructured polyelectrolyte multilayer drug delivery systems for bone metastasis prevention.

    PubMed

    Daubiné, Florence; Cortial, Delphine; Ladam, Guy; Atmani, Hassan; Haïkel, Youssef; Voegel, Jean-Claude; Clézardin, Philippe; Benkirane-Jessel, Nadia

    2009-10-01

    Polyelectrolyte multilayers (PEM) are well established nanoarchitectures with numerous potential applications, in particular as biomaterial coatings. They may exhibit specific biological properties in terms of controlled cell activation or local drug delivery. Here, in a new approach for bone metastasis prevention, we employed poly-l-lysine covalently grafted with beta-cyclodextrin as a polycationic vector (PLL-CD) for the antitumor bisphosphonate drug risedronate (RIS). Molar ratio for maximum loading of the PLL-CD vector with RIS was determined by Raman microspectroscopy. The efficacy of RIS at inhibiting cancer cell invasion in vitro was strongly enhanced upon complexation, whatever PLL-CD:RIS complexes were in solution or embedded into PEM nanoarchitectures. Complexes in solution also clearly prevented cancer-induced bone metastasis in animals. Incorporation of the complexes into PEM nanoarchitectures covering bone implants appears of interest for in situ prevention of bone metastasis after ablation.

  4. Migrastatin analogues target fascin to block tumour metastasis

    SciTech Connect

    Chen, L.; Jakoncic, J.; Yang, S.; Zhang, J.; Huang, X.Y.

    2010-04-15

    Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

  5. Ostomy metastasis after pull endoscopic gastrostomy: a unique favorable outcome.

    PubMed

    Fonseca, Jorge; Adriana, Carla; Fróis-Borges, Miguel; Meira, Tânia; Oliveira, Gabriel; Santos, José Carlos

    2015-04-01

    Head and neck cancer (HNC) patients tend to develop dysphagia. In order to preserve the nutritional support, many undergo endoscopic gastrostomy (PEG). In HNC patients, ostomy metastasis is considered a rare complication of PEG, but there are no reports of successful treatment of these metastatic cancers. We report the case of a 65 years old pharyngeal/laryngeal cancer patient who underwent a PEG before the neck surgery. He was considered to be cured, resumed oral intake and the PEG tube was removed. Ten months after, he returned with a metastasis at the ostomy site. A block resection of the stomach and abdominal wall was performed. Two years after the abdominal surgery, he is free of disease. Although usually considered a rare complication of the endoscopic gastrostomy, ostomy metastasis may be more frequent than usually considered and the present case report demonstrates that these patients may have a favourable outcome.

  6. Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers.

    PubMed

    Kruger, Thomas E; Miller, Andrew H; Godwin, Andrew K; Wang, Jinxi

    2014-02-01

    The mechanisms underlying malignant cell metastasis to secondary sites such as bone are complex and no doubt multifactorial. Members of the small integrin-binding ligand N-linked glycoproteins (SIBLINGs) family, particularly bone sialoprotein (BSP) and osteopontin (OPN), exhibit multiple activities known to promote malignant cell proliferation, detachment, invasion, and metastasis of several osteotropic cancers. The expression level of BSP and OPN is elevated in a variety of human cancers, particularly those that metastasize preferentially to the skeleton. Recent studies suggest that the "osteomimicry" of malignant cells is not only conferred by transmembrane receptors bound by BSP and OPN, but includes the "switch" in gene expression repertoire typically expressed in cells of skeletal lineage. Understanding the role of BSP and OPN in tumor progression, altered pathophysiology of bone microenvironment, and tumor metastasis to bone will likely result in development of better diagnostic approaches and therapeutic regimens for osteotropic malignant diseases.

  7. Transformation of Merkel cell carcinoma to ganglioneuroblastoma in intracranial metastasis.

    PubMed

    Lach, Boleslaw; Joshi, Sangeeta S; Murty, Naresh; Huq, Nasimul

    2014-09-01

    Merkel cell carcinoma is an aggressive neuroendocrine tumor occasionally demonstrating aberrant differentiation to other epithelial and nonepithelial cell lines. We describe a case of Merkel cell carcinoma displaying unique patterns of differentiation in the primary focus and brain metastasis. The skin primary was almost uniformly small cell carcinoma positive for epithelial and neuroendocrine markers, with a few glial fibrillary acidic protein- and cytokeratin 20-positive cells. The neoplasm contained giant cells immunoreactive for neurofilament and negative for epithelial markers. The neck lymph node metastasis was a typical neuroendocrine Merkel cell carcinoma positive for cytokeratin 20. A solitary dural intracranial metastasis displayed features of aggressive ganglioneuroblastoma, expressing many neuronal antigens with no evidence of glial or epithelial differentiation. After total gross resection, the tumor recurred within 3 months, and the patient developed skeletal metastases and died 6 months after craniotomy. PMID:24996688

  8. Blood–brain Barrier Remodeling during Brain Metastasis Formation

    PubMed Central

    Wrobel, Jagoda K; Toborek, Michal

    2016-01-01

    Our understanding of the process of metastatic progression has improved markedly over the past decades, yet metastasis remains the most enigmatic component of cancer pathogenesis. This lack of knowledge has serious health-related implications, since metastasis is responsible for 90% of all cancer-related mortalities. The brain is considered a sanctuary site for metastatic tumor growth, where the blood–brain barrier (BBB) and other components of the brain microenvironment, provide protection to the tumor cells from immune surveillance, chemotherapeutics and other potentially harmful substances. The interactions between tumor cells and the brain microenvironment, principally brain vascular endothelium, are the critical determinants in their progression toward metastasis, dormancy, or clearance. This review discusses current knowledge of the biology of metastatic progression, with a particular focus on the tumor cell migration and colonization in the brain.

  9. Blood–brain Barrier Remodeling during Brain Metastasis Formation

    PubMed Central

    Wrobel, Jagoda K; Toborek, Michal

    2016-01-01

    Our understanding of the process of metastatic progression has improved markedly over the past decades, yet metastasis remains the most enigmatic component of cancer pathogenesis. This lack of knowledge has serious health-related implications, since metastasis is responsible for 90% of all cancer-related mortalities. The brain is considered a sanctuary site for metastatic tumor growth, where the blood–brain barrier (BBB) and other components of the brain microenvironment, provide protection to the tumor cells from immune surveillance, chemotherapeutics and other potentially harmful substances. The interactions between tumor cells and the brain microenvironment, principally brain vascular endothelium, are the critical determinants in their progression toward metastasis, dormancy, or clearance. This review discusses current knowledge of the biology of metastatic progression, with a particular focus on the tumor cell migration and colonization in the brain. PMID:26837070

  10. Role of STAT3 in Cancer Metastasis and Translational Advances

    PubMed Central

    Patil, Prachi; Gude, Rajiv P.

    2013-01-01

    Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling. PMID:24199193

  11. Stereotactic body radiation therapy for metastasis to the adrenal glands.

    PubMed

    Shiue, Kevin; Song, Andrew; Teh, Bin S; Ellis, Rodney J; Yao, Min; Mayr, Nina A; Huang, Zhibin; Sohn, Jason; Machtay, Mitchell; Lo, Simon S

    2012-12-01

    Many primary cancers can metastasize to the adrenal glands. Adrenalectomy via an open or laparoscopic approach is the current definitive treatment, but not all patients are eligible or wish to undergo surgery. There are only limited studies on the use of conventional radiation therapy for palliation of symptoms from adrenal metastasis. However, the advent of stereotactic body radiation therapy (SBRT) - also named stereotactic ablative radiotherapy for primary lung cancer, metastases to the lung, and metastases to the liver - have prompted some investigators to consider the use of SBRT for metastases to the adrenal glands. This review focuses on the emerging data on SBRT of metastasis to the adrenal glands, while also providing a brief discussion of the overall management of adrenal metastasis.

  12. Implications of Hypoxia in Breast Cancer Metastasis to Bone

    PubMed Central

    Gilkes, Daniele M.

    2016-01-01

    Most solid tumors contain regions of hypoxia in which increased cell proliferation promotes increased oxygen consumption and the condition is further exacerbated as cancer cells become localized far from a functional blood vessel, further decreasing the oxygen supply. An important mechanism that promotes cell adaptation to hypoxic conditions is the expression of hypoxia-inducible factors (HIFs). Hypoxia-inducible factors transcriptionally regulate many genes involved in the invasion and metastasis of breast cancer cells. Patients, whose primary tumor biopsies show high HIF expression levels, have a greater risk of metastasis. The current review will highlight the potential role of hypoxia in breast cancer metastasis to the bone by considering the regulation of many steps in the metastatic process that include invasion, migration, margination and extravasation, as well as homing signals and regulation of the bone microenvironment. PMID:27706047

  13. Skin metastasis of hypopharyngeal carcinoma to the nasal tip.

    PubMed

    Shindo, Masahisa; Yoshida, Yuichi; Tominaga, Kyoko; Yamamoto, Osamu

    2013-06-01

    Head and neck squamous cell carcinoma (SCC) rarely metastasizes to the skin. Metastases to the nasal tip from hypopharyngeal malignancies are extremely rare. We present a patient with nasal tip metastasis from hypopharyngeal SCC. A 74-year-old man with hypopharyngeal and esophageal carcinomas had a red nodule on his nasal tip (so-called "clown nose"). Histopathologically, atypical squamoid cell nests had proliferated in a lobular fashion from the dermis to subcutaneous tissue. Those atypical cells were identical to primary tumor cells in the hypopharynx. Based on these findings, a diagnosis of skin metastasis from hypopharyngeal SCC was made. In patients with malignant disease, biopsy should be performed for any suspicious skin lesion. In a patient like ours, "clown nose" might be a symptom of cutaneous metastasis. When clinicians note a "clown nose", they should consider malignancies in the neck and chest areas.

  14. Patterns of Retropharyngeal Node Metastasis in Nasopharyngeal Carcinoma

    SciTech Connect

    Wang Xiaoshen; Hu Chaosu Ying Hongmei; Zhou Zhengrong; Ding Jianhui; Feng Yan

    2009-01-01

    Purpose: To explore the pattern of metastasis to retropharyngeal lymph nodes (RLN) and its relationship with tumor range in nasopharyngeal carcinoma (NPC) patients by using magnetic resonance imaging. Methods and Materials: Magnetic resonance images of 618 NPC patients were reviewed. Nodes were classified as metastatic on the basis of size criteria, the presence of nodal necrosis, and extracapsular spread. Results: A total of 597 involved RLN were detected in 392 patients (63.4%). The sites of RLN metastasis included occipital bone, 37 (6.2%); first cervical vertebra (C1), 453 (75.9%); second cervical vertebra (C2), 104 (17.4%); and third cervical vertebra (C3), 3 (0.5%). The incidence of RLN involvement was less than that of Level IIb node involvement (72.2% vs. 86.5%) in 543 patients with lymphadenopathy. The incidence of RLN metastasis was significantly higher in cases of parapharyngeal space invasion or involvement of Level II, Level III, Level IV, and/or Level V nodes and significantly lower in N0 and Stage I disease. Conversely, the incidence of RLN metastasis did not differ significantly among T1, 2, 3, and 4 disease or among Stage II, III, and IV disease. Conclusions: Level IIb nodes, rather than RLN, seem to be the first-echelon nodes in NPC. The incidence of RLN metastasis decreases steadily from level C1 to level C3. Retropharyngeal lymph node metastasis correlates well with involvement of the parapharyngeal space and metastases to Level II, III, IV, and/or V nodes but not with T stage.

  15. Galectin-3 as a Potential Target to Prevent Cancer Metastasis

    PubMed Central

    Ahmed, Hafiz; AlSadek, Dina M. M.

    2015-01-01

    Interactions between two cells or between cell and extracellular matrix mediated by protein–carbohydrate interactions play pivotal roles in modulating various biological processes such as growth regulation, immune function, cancer metastasis, and apoptosis. Galectin-3, a member of the β-galactoside-binding lectin family, is involved in fibrosis as well as cancer progression and metastasis, but the detailed mechanisms of its functions remain elusive. This review discusses its structure, carbohydrate-binding properties, and involvement in various aspects of tumorigenesis and some potential carbohydrate ligands that are currently investigated to block galectin-3 activity. PMID:26640395

  16. Ureteral Metastasis Secondary to Prostate Cancer: A Case Report

    PubMed Central

    Morales, I.; Bassa, C.; Pavlovic, A.; Morales, C.

    2015-01-01

    Prostate cancer is very frequent, but secondary ureteral metastasis are extremely rare. We present a 55 year old man with a 2 month history of right flank pain and lower urinary tract symptoms. Prostatic specific antigen of 11.3 ng/mL. Computed tomography showed right hydroureteronephrosis, a developing urinoma and right iliac adenopathies. He underwent right ureteronephrectomy, iliac lymphadenectomy and prostate biopsy. Pathology revealed prostatic carcinoma infiltrating the ureteral muscularis propria, without mucosal involvement. There are 46 reported cases of prostate cancer with ureteral metastases. Ureteral metastasis are a rare cause of renal colic and need of a high index of suspicion. PMID:26793587

  17. Phase transitions in tumor growth: III vascular and metastasis behavior

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, J. A.; Cocho, G.; Mansilla, R.; Nieto-Villar, José Manuel

    2016-11-01

    We propose a mechanism for avascular, vascular and metastasis tumor growth based on a chemical network model. Vascular growth and metastasis, appear as a hard phase transition type, as "first order", through a supercritical Andronov-Hopf bifurcation, emergence of limit cycle and then through a cascade of bifurcations type saddle-foci Shilnikov's bifurcation. Finally, the thermodynamics framework developed shows that the entropy production rate, as a Lyapunov function, indicates the directional character and stability of the dynamical behavior of tumor growth according to this model.

  18. MicroRNAs in the Regulation of MMPs and Metastasis

    PubMed Central

    Abba, Mohammed; Patil, Nitin; Allgayer, Heike

    2014-01-01

    MicroRNAs are integral molecules in the regulation of numerous physiological cellular processes including cellular differentiation, proliferation, metabolism and apoptosis. Their function transcends normal physiology and extends into several pathological entities including cancer. The matrix metalloproteinases play pivotal roles, not only in tissue remodeling, but also in several physiological and pathological processes, including those supporting cancer progression. Additionally, the contribution of active MMPs in metastatic spread and the establishment of secondary metastasis, via the targeting of several substrates, are also well established. This review focuses on the important miRNAs that have been found to impact cancer progression and metastasis through direct and indirect interactions with the matrix metalloproteinases. PMID:24670365

  19. Solitary thyroid metastasis from clear-cell renal carcinoma.

    PubMed Central

    Madore, P.; Lan, S.

    1975-01-01

    A 58-year-old woman underwent nephrectomy because of clear-cell renal carcinoma. Seven years later a solitary thyroid metastasis was detected. She is alive and well 17 months after thyroidectomy. The rarity of this manifestation is well known but its explanation is not clear. The long metastasis-free interval, a characteristic shared by other hormonally dependent neoplasms, has been explained in part by the concept of "dormant cells", which do not undergo division. The stimulus that provokes these cells into division is at present not known. Images FIG. 1 FIG. 2 PMID:1122443

  20. Regional but fatal: Intraperitoneal metastasis in gastric cancer.

    PubMed

    Wei, Jia; Wu, Nan-Die; Liu, Bao-Rui

    2016-09-01

    Peritoneal carcinomatosis appears to be the most common pattern of metastasis or recurrence and is associated with poor prognosis in gastric cancer patients. Many efforts have been made to improve the survival in patients with peritoneal metastasis. Hyperthermic intraperitoneal chemotherapy remains a widely accepted strategy in the treatment of peritoneal dissemination. Several phase II-III studies confirmed that the combined cytoreducitve surgery and hyperthermic intraperitoneal chemotherapy resulted in longer survival in patients with peritoneal carcinomatosis. In addition, proper selection and effective regional treatment in patients with high risk of peritoneal recurrence after resection will further improve prognosis in local advanced gastric cancer patients. PMID:27672270

  1. Regional but fatal: Intraperitoneal metastasis in gastric cancer

    PubMed Central

    Wei, Jia; Wu, Nan-Die; Liu, Bao-Rui

    2016-01-01

    Peritoneal carcinomatosis appears to be the most common pattern of metastasis or recurrence and is associated with poor prognosis in gastric cancer patients. Many efforts have been made to improve the survival in patients with peritoneal metastasis. Hyperthermic intraperitoneal chemotherapy remains a widely accepted strategy in the treatment of peritoneal dissemination. Several phase II-III studies confirmed that the combined cytoreducitve surgery and hyperthermic intraperitoneal chemotherapy resulted in longer survival in patients with peritoneal carcinomatosis. In addition, proper selection and effective regional treatment in patients with high risk of peritoneal recurrence after resection will further improve prognosis in local advanced gastric cancer patients. PMID:27672270

  2. The “Sharp” blade against HIF-mediated metastasis

    PubMed Central

    Amelio, Ivano; Melino, Gerry

    2012-01-01

    Hypoxia-inducible factors (HIFs) control cellular adaptation to oxygen deprivation. Cancer cells engage HIFs to sustain their growth in adverse conditions, thus promoting a cellular reprograming that includes metabolism, proliferation, survival and mobility. HIFs overexpression in human cancer biopsies correlates with high metastasis and mortality. A recent report has elucidated a novel mechanism for HIFs regulation in triple-negative breast cancer. Specifically, the basic helix-loop-helix (bHLH), Sharp-1, serves HIF1α to the proteasome and promotes its O2-indendpendet degradation, counteracting HIF-mediated metastasis. These findings shed light on how HIFs are manipulated during cancer pathogenesis. PMID:23187809

  3. Regional but fatal: Intraperitoneal metastasis in gastric cancer

    PubMed Central

    Wei, Jia; Wu, Nan-Die; Liu, Bao-Rui

    2016-01-01

    Peritoneal carcinomatosis appears to be the most common pattern of metastasis or recurrence and is associated with poor prognosis in gastric cancer patients. Many efforts have been made to improve the survival in patients with peritoneal metastasis. Hyperthermic intraperitoneal chemotherapy remains a widely accepted strategy in the treatment of peritoneal dissemination. Several phase II-III studies confirmed that the combined cytoreducitve surgery and hyperthermic intraperitoneal chemotherapy resulted in longer survival in patients with peritoneal carcinomatosis. In addition, proper selection and effective regional treatment in patients with high risk of peritoneal recurrence after resection will further improve prognosis in local advanced gastric cancer patients.

  4. Retroperitoneal cystic metastasis from a small clear cell renal carcinoma.

    PubMed

    Ishii, N; Yonese, J; Tsukamoto, T; Maezawa, T; Ishikawa, Y; Fukui, I

    2001-11-01

    A 39-year-old housewife was referred to our hospital for the treatment of a small renal tumor. A 25 x 35 mm cystic mass that had been detected by computerized tomography scan just caudal to the renal hilus proved to be a metastasis from the renal carcinoma of clear cell type. The pathogenesis may have been due to tumor cells obstructing a lymphatic vessel draining the kidney. Cystic metastasis from renal cell carcinoma is very rare and this appears to be the second published case in the world.

  5. An Unusual Case of Gastric Cancer Presenting with Breast Metastasis with Pleomorphic Microcalcifications

    PubMed Central

    Ka, Solomon Yig Joon; Lo, Sherwin Shing Wai; Chu, Chi Yeung; Ma, Ming Wai

    2012-01-01

    Breast metastasis from gastric carcinoma is rare. We present a case of right breast mass with microcalcification in which the diagnosis of poorly differentiated adenocarcinoma from the stomach was made after a biopsy. Pleomorphic microcalcification was noted in the ill-defined breast mass, which is a rare feature in breast metastasis. Since breast metastasis usually signifies advanced metastatic disease, differentiating primary breast cancer from metastasis is important for appropriate treatment. PMID:23091550

  6. Metachronous Bilateral Isolated Adrenal Metastasis from Rectal Adenocarcinoma: A Case Report

    PubMed Central

    Jabir, H.; Tawfiq, N.; Moukhlissi, M.; Akssim, M.; Guensi, A.; Kadiri, B.; Bouchbika, Z.; Taleb, A.; Benchekroun, N.; Jouhadi, H.; Sahraoui, S.; Zamiati, S.; Benider, A.

    2014-01-01

    We report a case of adrenal metastasis from colorectal cancer in a 54-year-old woman. Nine months after resection for advanced rectal carcinoma, a computed tomography scan revealed bilateral adrenal metastasis. The level of serum carcinoembryonic antigen was normal. A bilateral adrenalectomy was performed after chemotherapy. Histopathological examination showed adenocarcinoma, compatible with metastasis from the rectal cancer. Adrenal metastasis should be considered in the patients' follow-up for colorectal cancer. PMID:24860684

  7. Ethmoid metastasis of endometrial carcinoma causing mucocoele of maxillary antrum.

    PubMed

    Scott, A; Raine, M; Stansbie, J M

    1998-03-01

    We report a case of an antral mucocoele secondary to the obstruction of its ostium by metastatic endometrial carcinoma. This is the first report of such a cause for a mucocoele, and for a metastasis from such a tumour in the head and neck.

  8. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis.

    PubMed

    Huang, Yujie; Song, Nan; Ding, Yanping; Yuan, Shaopeng; Li, Xuhui; Cai, Hongchen; Shi, Hubing; Luo, Yongzhang

    2009-10-01

    Before metastasis, certain organs have already been influenced by primary tumors. However, the exact alterations and regulatory mechanisms of the premetastatic organs remain poorly understood. Here, we report that, in the premetastatic stage, angiopoietin 2 (Angpt2), matrix metalloproteinase (MMP) 3, and MMP10 are up-regulated in the lung by primary B16/F10 tumor, which leads to the increased permeability of pulmonary vasculatures and extravasation of circulating tumor cells. Subsequent studies show that Angpt2, MMP3, and MMP10 have a synergistic effect on disrupting vascular integrity in both in vitro and in vivo models. Lentivirus-based in vivo RNA interference of Angpt2, MMP3, and MMP10 attenuates the pulmonary vascular permeability and suppresses the infiltration of myeloid cells in the premetastatic lung. Moreover, knocking down these factors significantly inhibits the spontaneous lung metastasis in the model by orthotopic implantation of MDA-MB-231-Luc-D3H1 cells in nude mice. Further investigations reveal that the malignancy of tumor cells is positively correlated with their capabilities to induce the expression of Angpt2, MMP3, and MMP10. Luciferase reporter assay and chromatin immunoprecipitation assay also suggest that transforming growth factor-beta1 and tumor necrosis factor-alpha signaling are involved in the regulation of these premetastatic factors. Our study shows that pulmonary vascular destabilization in the premetastatic phase promotes the extravasation of tumor cells and facilitates lung metastasis, which may provide potential targets for clinical prevention of metastasis. PMID:19773447

  9. Tungsten targets the tumor microenvironment to enhance breast cancer metastasis.

    PubMed

    Bolt, Alicia M; Sabourin, Valérie; Molina, Manuel Flores; Police, Alice M; Negro Silva, Luis Fernando; Plourde, Dany; Lemaire, Maryse; Ursini-Siegel, Josie; Mann, Koren K

    2015-01-01

    The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients' years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans. PMID:25324207

  10. Tungsten Targets the Tumor Microenvironment to Enhance Breast Cancer Metastasis

    PubMed Central

    Bolt, Alicia M.; Sabourin, Valérie; Molina, Manuel Flores; Police, Alice M.; Negro Silva, Luis Fernando; Plourde, Dany; Lemaire, Maryse; Ursini-Siegel, Josie; Mann, Koren K.

    2015-01-01

    The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients’ years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans. PMID:25324207

  11. Gene Expression Profiling of Breast Cancer Brain Metastasis

    PubMed Central

    Lee, Ji Yun; Park, Kyunghee; Lee, Eunjin; Ahn, TaeJin; Jung, Hae Hyun; Lim, Sung Hee; Hong, Mineui; Do, In-Gu; Cho, Eun Yoon; Kim, Duk-Hwan; Kim, Ji-Yeon; Ahn, Jin Seok; Im, Young-Hyuck; Park, Yeon Hee

    2016-01-01

    The biology of breast cancer brain metastasis (BCBM) is poorly understood. We aimed to explore genes that are implicated in the process of brain metastasis of primary breast cancer (BC). NanoString nCounter Analysis covering 252 target genes was used for comparison of gene expression levels between 20 primary BCs that relapsed to brain and 41 BCBM samples. PAM50-based intrinsic subtypes such as HER2-enriched and basal-like were clearly over-represented in BCBM. A panel of 22 genes was found to be significantly differentially expressed between primary BC and BCBM. Five of these genes, CXCL12, MMP2, MMP11, VCAM1, and MME, which have previously been associated with tumor progression, angiogenesis, and metastasis, clearly discriminated between primary BC and BCBM. Notably, the five genes were significantly upregulated in primary BC compared to BCBM. Conversely, SOX2 and OLIG2 genes were upregulated in BCBM. These genes may participate in metastatic colonization but not in primary tumor development. Among patient-matched paired samples (n = 17), a PAM50 molecular subtype conversion was observed in eight cases (47.1%), with a trend toward unfavorable subtypes in patients with the distinct gene expression. Our findings, although not conclusive, reveal differentially expressed genes that might mediate the brain metastasis process. PMID:27340107

  12. [Treatment of liver metastasis of endocrine tumors of the pancreas].

    PubMed

    Orozco Zepeda, H

    1997-01-01

    The aim of this review article is to analyze the diagnostic approach, presentation and therapeutic modalities in patients with liver metastasis from endocrine tumors. The paper shows the "state of the art" of therapeutic approaches with emphasis on the roll of different surgery, radio and chemotherapy, arterial embolization and other palliative procedures. The overall results of each of this modalities are also shown.

  13. A New Paradigm for Mechanobiological Mechanisms in Tumor Metastasis

    PubMed Central

    Torzilli, Peter A.; Bourne, Jonathan W.; Cigler, Tessa; Vincent, C.Theresa

    2012-01-01

    Tumor metastases and epithelial to mesenchymal transition (EMT) involve tumor cell invasion and migration through the dense collagen-rich extracellular matrix surrounding the tumor. Little is known about the mechanobiological mechanisms involved in this process, nor the role of the mechanical forces generated by the cells in their effort to invade and migrate through the stroma. In this paper we propose a new fundamental mechanobiological mechanism involved in cancer growth and metastasis, which can be both protective or destructive depending on the magnitude of the forces generated by the cells. This new mechanobiological mechanism directly challenges current paradigms that are focused mainly on biological and biochemical mechanisms associated with tumor metastasis. Our new mechanobiological mechanism describes how tumor expansion generates mechanical forces within the stroma to not only resist tumor expansion but also inhibit or enhance tumor invasion by, respectively, inhibiting or enhancing matrix metalloproteinase (MMP) degradation of the tensed interstitial collagen. While this mechanobiological mechanism has not been previously applied to the study of tumor metastasis and EMT, it may have the potential to broaden our understanding of the tumor invasive process and assist in developing new strategies for preventing or treating cancer metastasis. PMID:22613484

  14. MMP-13 is involved in oral cancer cell metastasis

    PubMed Central

    Huang, Shun-Hong; Law, Ching-Hsuan; Kuo, Ping-Hsueh; Hu, Ren-Yu; Yang, Ching-Chieh; Chung, Ting-Wen; Li, Ji-Min; Lin, Li-Hsun; Liu, Yi-Chung; Liao, En-Chi; Tsai, Yi-Ting; Wei, Yu-Shan; Lin, Chi-Chen; Chang, Chien-Wen; Chou, Hsiu-Chuan; Wang, Wen-Ching; Chang, Margaret Dah-Tsyr; Wang, Lu-Hai; Kung, Hsing-Jien; Chan, Hong-Lin; Lyu, Ping-Chiang

    2016-01-01

    The oral cancer cell line OC3-I5 with a highly invasive ability was selected and derived from an established OSCC line OC3. In this study, we demonstrated that matrix metalloproteinases protein MMP-13 was up-regulated in OC3-I5 than in OC3 cells. We also observed that expression of epithelial–mesenchymal transition (EMT) markers including Twist, p-Src, Snail1, SIP1, JAM-A, and vinculin were increased in OC3-I5 compared to OC3 cells, whereas E-cadherin expression was decreased in the OC3-I5 cells. Using siMMP-13 knockdown techniques, we showed that siMMP-13 not only reduced the invasion and migration, but also the adhesion abilities of oral cancer cells. In support of the role of MMP-13 in metastasis, we used MMP-13 expressing plasmid-transfected 293T cells to enhance MMP-13 expression in the OC3 cells, transplanting the MMP-13 over expressing OC3 cells into nude mice led to enhanced lung metastasis. In summary, our findings show that MMP-13 promotes invasion and metastasis in oral cancer cells, suggesting altered expression of MMP-13 may be utilized to impede the process of metastasis. PMID:26958809

  15. Rad51 supports triple negative breast cancer metastasis

    PubMed Central

    Wiegmans, Adrian P; Al-Ejeh, Fares; Chee, Nicole; Yap, Pei-Yi; Gorski, Julia J; Silva, Leonard Da; Bolderson, Emma; Chenevix-Trench, Georgia; Anderson, Robin; Simpson, Peter T; Lakhani, Sunil R; Khanna, Kum Kum

    2014-01-01

    In contrast to extensive studies on familial breast cancer, it is currently unclear whether defects in DNA double strand break (DSB) repair genes play a role in sporadic breast cancer development and progression. We performed analysis of immunohistochemistry in an independent cohort of 235 were sporadic breast tumours. This analysis suggested that RAD51 expression is increased during breast cancer progression and metastasis and an oncogenic role for RAD51 when deregulated. Subsequent knockdown of RAD51 repressed cancer cell migration in vitro and reduced primary tumor growth in a syngeneic mouse model in vivo. Loss of RAD51 also inhibited associated metastasis not only in syngeneic mice but human xenografts and changed the metastatic gene expression profile of cancer cells, consistent with inhibition of distant metastasis. This demonstrates for the first time a new function of RAD51 that may underlie the proclivity of patients with RAD51 overexpression to develop distant metastasis. RAD51 is a potential biomarker and attractive drug target for metastatic triple negative breast cancer, with the capability to extend the survival of patients, which is less than 6 months. PMID:24811120

  16. Palliation of Painful Perineal Metastasis Treated with Radiofrequency Thermal Ablation

    SciTech Connect

    Thanos, L. Mylona, S.; Kalioras, V.; Pomoni, M.; Batakis, N.

    2005-04-15

    We report a case of painful perineal metastasis from urinary bladder carcinoma in a 73-years-old woman, treated with CT-guided radiofrequency ablation (RFA). The pain was immediately relieved and follow-up at 1 and 6 months showed total necrosis of the mass. One year later, the patient has no pain and her quality of life is improved.

  17. Primary pulmonary carcinoid tumor with metastasis to endometrial polyp

    PubMed Central

    Momeni, Mazdak; Kolev, Valentin; Costin, Dan; Mizrachi, Howard H.; Chuang, Linus; Warner, Richard R.P.; Gretz, Herbert F.

    2012-01-01

    INTRODUCTION A carcinoid tumor occurring in the endometrium has been documented in the literature, but there is no report in regard to carcinoid tumor metastasis to endometrium. PRESENTATION OF CASE We report a case of a malignant carcinoid metastasis to an endometrial polyp. Patient underwent hysteroscopy, and polypectomy. The pathology demonstrated an endometrial polyp containing a 4 mm x 5 mm nodule of metastatic carcinoid tumor, consistent with metastasis from patient's known pulmonary carcinoid. The tumor was morphologically similar to the tumors of the right lung, with similar immune-profile. DISCUSSION This patient presented with a suspicious pelvic ultrasound. Due to her age, the first priority was to exclude uterine cancer. The endometrial polyp, which was found, had a small focus of metastatic carcinoid tumor. To the best of our knowledge, this finding has not been previously recorded in the literature. Our patient also had a history of metastatic carcinoid tumor to breast. This finding is also very uncommon. CONCLUSION This is the first case in the literature described a malignant carcinoid metastasis to an endometrial polyp. PMID:23127865

  18. Cutaneous metastasis from gastrointestinal adenocarcinoma of unknown primary origin.

    PubMed

    Junqueira, Ana Lucia Ariano; Corbett, Ana Maria França; Oliveira Filho, Jayme de; Nasser, Kassila da Rosa; Haddad, Natalie Nejem; Tebet, Ana Carolina Franco

    2015-01-01

    Cutaneous metastasis is a rare manifestation of visceral malignancies that indicates primarily advanced disease. Due to its low incidence and similarity to other cutaneous lesions, it is not uncommon to have a delayed diagnosis and a shortened prognosis. We describe the case of a patient who presented with a cutaneous nodule in the sternal region as a first sign of malignancy.

  19. Carcinoid syndrome from gastrointestinal carcinoids without liver metastasis.

    PubMed

    Feldman, J M; Jones, R S

    1982-07-01

    Although patients with bronchial and ovarian carcinoid tumors can develop the carcinoid syndrome (diarrhea and/or flushing) in the absence of hepatic metastasis, it is believed that development of the carcinoid syndrome in patients with carcinoid tumors of gastrointestinal origin occurs only after the patient has hepatic metastasis. This is explained by hepatic inactivation of most of the serotonin in the portal circulation or by the fact that hepatic metastases are larger than the primary tumor in the gastrointestinal tract. Three patients with ileal and jejunal carcinoid tumors who developed the carcinoid syndrome without obvious hepatic metastasis are described. Two of the patients had intra-abdominal, but extrahepatic, metastasis that probably drained directly into the systemic circulation. The third patient had an ileal carcinoid with clinical involvement limited to adjacent mesenteric lymph nodes. Following resection of her tumor, her urinary 5-HIAA excretion and platelet serotonin level returned to normal, and her attacks of carcinoid flushing virtually ceased. She has occasional spells of "blushing" that are thought to be benign; however, further close follow-up study will be needed to be certain that she is free of disease. It is suggested that each patient with the carcinoid syndrome be evaluated with CT and technetium-99 pertechnetate liver scans. If there is no liver involvement detected with these studies, one should consider hepatic arteriogram or laparotomy to determine if the patient's tumor might be totally resectable. PMID:7092350

  20. Oxygen and Metastasis: A Conversation with Dr. Nick Restifo

    Cancer.gov

    Dr. Nick Restifo, a senior investigator in NCI’s Center for Cancer Research, discusses his recently published study finding that Oxygen, a molecule necessary for life, paradoxically aids cancer metastasis to the lung by impairing cancer-killing immune cells.

  1. Cervical metastasis on level IV in laryngeal cancer.

    PubMed

    Furtado de Araújo Neto, V J; Cernea, C R; Aparecido Dedivitis, R; Furtado de Araújo Filho, V J; Fabiano Palazzo, J; Garcia Brandão, L

    2014-02-01

    The presence of cervical metastasis has substantial negative impact on survival of patients with laryngeal cancer. Bilateral elective selective neck dissection of levels II, III and IV is usually the chosen approach in these patients. However, there is significant morbidity associated with level IV dissection, such as phrenic nerve injury and lymphatic fistula. The objective of the present study was to evaluate the frequency of metastatic nodes in level IV in clinically T3/T4N0 patients with laryngeal cancer. The pathological reports of 77 patients with clinically T3/T4N0 laryngeal squamous cell carcinoma were reviewed. Patients underwent bilateral lateral neck dissection from January 2007 to November 2012. The surgical specimens were subdivided in levels before evaluation. There were 12 patients with neck metastasis (15.58%). In 3 cases (3.89%), there were metastatic lymph nodes in level IV, all T4 and with ipsilateral metastasis. In conclusion, the incidence of level IV metastasis was 3.89%, an in all patients was staged as T4.

  2. Imaging of an adrenal cortical carcinoma and its skeletal metastasis

    SciTech Connect

    Drane, W.E.; Graham, M.M.; Nelp, W.B.

    1983-08-01

    Though the typical scintigraphic appearance in adrenal cortical carcinoma is bilateral nonvisualization of the adrenal glands, a case with simultaneous visualization of both an adrenal cortical carcinoma and its skeletal metastasis using 6-..beta..-(/sup 131/I)iodomethyl-19-norcholesterol is reported.

  3. Imaging of an adrenal cortical carcinoma and its skeletal metastasis

    SciTech Connect

    Drane, W.E.; Graham, M.M.; Nelp, W.B.

    1983-08-01

    Though the typical scintigraphic appearance in adrenal cortical carcinoma is bilateral nonvisualization of the adrenal glands, we report a case with simultaneous visualization of both an adrenal cortical carcinoma and its skeletal metastasis using 6-beta-(/sup 131/I)iodomethyl-19-norcholesterol.

  4. Tungsten targets the tumor microenvironment to enhance breast cancer metastasis.

    PubMed

    Bolt, Alicia M; Sabourin, Valérie; Molina, Manuel Flores; Police, Alice M; Negro Silva, Luis Fernando; Plourde, Dany; Lemaire, Maryse; Ursini-Siegel, Josie; Mann, Koren K

    2015-01-01

    The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients' years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans.

  5. TWIST1 and BMI1 in Cancer Metastasis and Chemoresistance

    PubMed Central

    Ren, Hong; Du, Peizhun; Ge, Zongyu; Jin, Yiting; Ding, Di; Liu, Xiuping; Zou, Qiang

    2016-01-01

    Purpose Increasing evidences revealed that cancer cells with the characteristics of epithelial-mesenchymal transition (EMT) or cancer stem cells (CSC) have high ability of progression, invasion, metastasis and chemoresistance. TWIST1 and BMI1 are crucial transcription factors required for EMT and CSC. Both TWIST1 and BMI1 are up-regulated in various cancers and have a positive correlation with poor prognosis. Although recent results showed that the two molecules function in promoting cancer metastasis and chemoresistance respectively, the correlation of TWIST1 and BMI1 is not well understood. Methods In this review, we summarize recent advance in cancer research focus on TWIST1 and BMI1 in cancer metastasis and chemoresistance, and emphasize the possible link between EMT and CSC. Results Further investigation of TWIST1 and BMI1 cooperately promote CSC proliferation due to EMT-associated effect will help to understand the mechanism of tumor cells metastasis and chemoresistance. Conclusions TWIST1 and BMI1 in cancer cells will be effective targets for treating chemoresistant metastatic lesions. PMID:27326250

  6. Immunosuppressive cells in tumor immune escape and metastasis.

    PubMed

    Liu, Yang; Cao, Xuetao

    2016-05-01

    Tumor immune escape and the initiation of metastasis are critical steps in malignant progression of tumors and have been implicated in the failure of some clinical cancer immunotherapy. Tumors develop numerous strategies to escape immune surveillance or metastasize: Tumors not only modulate the recruitment and expansion of immunosuppressive cell populations to develop the tumor microenvironment or pre-metastatic niche but also switch the phenotype and function of normal immune cells from a potentially tumor-reactive state to a tumor-promoting state. Immunosuppressive cells facilitate tumor immune escape by inhibiting antitumor immune responses and furthermore promote tumor metastasis by inducing immunosuppression, promoting tumor cell invasion and intravasation, establishing a pre-metastatic niche, facilitating epithelial-mesenchymal transition, and inducing angiogenesis at primary tumor or metastatic sites. Numerous translational studies indicate that it is possible to inhibit tumor immune escape and prevent tumor metastasis by blocking immunosuppressive cells and eliminating immunosuppressive mechanisms that are induced by either immunosuppressive cells or tumor cells. Furthermore, many clinical trials targeting immunosuppressive cells have also achieved good outcome. In this review, we focus on the underlying mechanisms of immunosuppressive cells in promoting tumor immune escape and metastasis, discuss our current understanding of the interactions between immunosuppressive cells and tumor cells in the tumor microenvironment, and suggest future research directions as well as potential clinical strategies in cancer immunotherapy.

  7. Brain Metastasis in Patients With Adrenocortical Carcinoma: A Clinical Series

    PubMed Central

    Tageja, Nishant; Rosenberg, Avi; Mahalingam, Sowmya; Quezado, Martha; Velarde, Margarita; Edgerly, Maureen; Fojo, Tito

    2015-01-01

    Introduction: Adrenocortical carcinoma (ACC) is a heterogeneous and rare disease. At presentation or at the time of a recurrence, the disease commonly spreads to the liver, lungs, lymph nodes, and bones. The brain has only rarely been reported as a site of metastases. Objective: The aims of this report were to describe the clinical characteristics of patients with ACC who developed brain metastasis and were evaluated at the National Cancer Institute. Methods: We describe the history and clinical presentation of six patients with ACC and metastatic disease in the brain. Images of the six patients and pathology slides were reviewed when available. Results: The median age at the time of the diagnosis of ACC was 42 years. The median time from the initial diagnosis until the presentation of brain metastasis was 43 months. As a group the patients had previously received multiples lines of chemotherapy (median of three), and they presented with one to three metastatic brain lesions. Four patients underwent metastasectomy, one had radiosurgery, and one had both modalities. Two patients are still alive, three died, between 2 and 14 months after the diagnosis of brain metastases, and one was lost to follow-up. Conclusion: Patients with advanced ACC can rarely present with metastasis to the brain, most often long after the initial diagnosis. Timely diagnosis of brain metastasis with appropriate intervention after discussion in a multidisciplinary meeting can improve the prognosis in this particular scenario. PMID:25412413

  8. Ventriculoperitoneal shunt for hydrocephalus caused by central nervous system metastasis.

    PubMed

    Lee, Seung Hoon; Kong, Doo Sik; Seol, Ho Joon; Nam, Do-Hyun; Lee, Jung-Il

    2011-09-01

    The development of better diagnostic tools and therapeutic modalities has increased the incidence of central nervous system (CNS) metastasis in malignant tumor patients. Hydrocephalus can result from CNS metastasis and frustrate cancer treatment. The authors sought to investigate the outcomes and the roles of ventriculoperitoneal shunts (VPS) in patients with CNS metastasis. The medical records of 50 consecutive patients who underwent VPS for hydrocephalus related to CNS metastasis were analyzed retrospectively. Data included features of primary malignancies, CNS involvement, clinical course and surgical outcome. Median patient age was 55.0 years (range 25-77), and 30 female and 20 male patients were included in the study. At the time of VPS, 10 patients had parenchymal metastases only and 40 patients had leptomeningeal seeding (LMS). Symptom improvement was observed postoperatively in 40 patients (80%), mean Karnofsky performance status (KPS) scale change was from 37.8 to 46.0, and median survival from VPS was 3.0 months (2 days to 54 months). A ventricular opening pressure of >30 cmH(2)O (HR 6.44, 95% CI 1.26-32.9, P = 0.02) and further cancer treatment after VPS (HR 0.17, 95% CI 0.07-0.42, P < 0.0001) were found to be independent risk factors of poorer and better survival, respectively. Hydrocephalus in CNS metastasis requiring VPS is commonly associated with LMS. VPS is an effective palliative measure and an adequate cancer treatment after VPS may provide the best means of improving survival.

  9. Survivin Is a Potential Mediator of Prostate Cancer Metastasis

    SciTech Connect

    Zhang Min; Coen, John J.; Khor, Li-Yan; Pollack, Alan; Zhang Yifen; Zietman, Anthony L.; Shipley, William U.

    2010-11-15

    Purpose: We examined whether Survivin expression is associated with an increased risk of metastasis in prostate cancer. Methods and Materials: A total of 205 patients with T1 (23%) and T2 (77%) prostate cancer were treated with conventional external beam radiation therapy from 1991 to 1993 at the Massachusetts General Hospital. Of the patients, 62 had adequate and suitable-stained tumor material for Survivin analysis. Median follow-up was 102 months (range, 5-127 months). Distant failure was determined on the basis of clinical criteria. In preclinical studies, replication-deficient adenovirus encoding phosphorylation-defective Survivin Thr34{yields}Ala dominant-negative mutant pAd-S(T34A) or short hairpin RNA (shRNA) was used to inhibit Survivin in prostate cancer models, and the cell motility, morphology, and metastasis were investigated. Results: Our correlative data on men with early-stage (T1/T2) prostate cancers treated at Massachusetts General Hospital by definitive radiotherapy indicated that overexpression of Survivin (positive staining in {>=}10% cells) was associated with a significantly increased risk for the subsequent development of distant metastasis (p = 0.016) in the univariate analysis. In the multivariate analysis, overexpression of Survivin remained an independent predictor of distant metastasis (p = 0.008). The inhibition of Survivin dramatically inhibited invasiveness of prostate cancer cells in the in vitro invasion assay and spontaneous metastasis in the Dunning prostate cancer in vivo model. Furthermore, attenuation of Survivin resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Conclusions: This study suggests that Survivin may be a potentially important prognostic marker and promising therapeutic target in metastatic prostate cancer.

  10. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages

    PubMed Central

    Kitamura, Takanori; Qian, Bin-Zhi; Soong, Daniel; Cassetta, Luca; Noy, Roy; Sugano, Gaël; Kato, Yu; Li, Jiufeng

    2015-01-01

    Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM–cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets. PMID:26056232

  11. A case of symptomatic synchronous cervical and cerebellar metastasis after resection of thoracal metastasis from temporal glioblastoma multiforme without any local recurrence

    PubMed Central

    Karatas, Yasar; Cengiz, Sahika Liva; Ustun, Mehmet Erkan

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and the most malignant primary intracranial tumor in adults and it is usually occurs between the age of 40 and 60 years. It is local invasive and recurrent tumor and hence that has a poor prognosis. However, recent advances in tumor surgery, irradiation and chemotherapeutic agent permit long survival and metastasis which is symptomatic. Previously studies reported spinal metastasis, but we report a first case of synchronous symptomatic cerebellar and cervical spinal metastasis after resection of symptomatic thoracic spinal metastasis from temporal GBM without any recurrence of excision areas.

  12. A case of symptomatic synchronous cervical and cerebellar metastasis after resection of thoracal metastasis from temporal glioblastoma multiforme without any local recurrence

    PubMed Central

    Karatas, Yasar; Cengiz, Sahika Liva; Ustun, Mehmet Erkan

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and the most malignant primary intracranial tumor in adults and it is usually occurs between the age of 40 and 60 years. It is local invasive and recurrent tumor and hence that has a poor prognosis. However, recent advances in tumor surgery, irradiation and chemotherapeutic agent permit long survival and metastasis which is symptomatic. Previously studies reported spinal metastasis, but we report a first case of synchronous symptomatic cerebellar and cervical spinal metastasis after resection of symptomatic thoracic spinal metastasis from temporal GBM without any recurrence of excision areas. PMID:27695566

  13. Colorectal cancer manifesting with metastasis to prolactinoma: report of a case involving symptoms mimicking pituitary apoplexy.

    PubMed

    Thewjitcharoen, Yotsapon; Shuangshoti, Shanop; Lerdlum, Sukalaya; Siwanuwatn, Rungsak; Sunthornyothin, Sarat

    2014-01-01

    Pituitary metastasis is an uncommon first presentation of systemic malignancy. The most common presenting symptom of pituitary metastasis is diabetes insipidus reflecting involvement of the stalk and/or posterior pituitary. We herein present a unique case of the coexistence of both a functioning pituitary adenoma (prolactinoma) and pituitary metastasis of advanced colorectal cancer with pituitary apoplexy as the first manifestation of underlying malignancy. The present case emphasizes the need to consider pituitary metastasis as a differential diagnosis in patients presenting with pituitary lesions and be aware that tumor-to-tumor metastasis can occur unexpectedly in those with pituitary metastases.

  14. Signaling pathways in breast cancer metastasis - novel insights from functional genomics

    PubMed Central

    2011-01-01

    The advent of genomic profiling technology has brought about revolutionary changes in our understanding of breast cancer metastasis. Gene expression analyses of primary tumors have been used to predict metastatic propensity with high accuracy. Animal models of metastasis additionally offer a platform to experimentally dissect components of the metastasis genetic program. Recent integrated studies have synergized clinical bioinformatic analyses with advanced experimental methodology and begun to uncover the identities and dynamics of signaling programs driving breast cancer metastasis. Such functional genomics studies hold great promise for understanding the genetic basis of metastasis and improving therapeutics for advanced diseases. PMID:21457525

  15. Metastasis to the pancreas and the spleen: an increasing diagnostic and therapeutic challenge

    PubMed Central

    Jesús Fernández-Aceñero, M.; Abengózar Muela, Marta; Chaves Portela, Sara; Wolfgang Vorwald, Peter

    2011-01-01

    We have reviewed the electronic biopsies database files of the Department of Surgical Pathology, Fundación Jiménez Díaz in Madrid (Spain). In this time period (1998–2010) we have found 3 pancreatic metastasis and 5 splenic metastasis. Two of the pancreatic metastases were originated in clear cell renal cell carcinomas. The last pancreatic metastasis was from a malignant cutaneous melanoma diagnosed and treated 8 years before. As for splenic metastasis, three of them were diagnosed during the abdominal surgery for primary therapy of the tumour (2 ovaries and one endometrium), while the remaining 2 corresponded to metastasis from a lung primary diagnosed 1 year before and a colonic primary diagnosed 6 years before. The patients with splenic metastasis died on the short term with progression of the disease despite resection of the splenic lesions, while the patients with pancreatic metastasis have survived longer. PMID:24765305

  16. Effect of Chronic Psychological Stress on Liver Metastasis of Colon Cancer in Mice.

    PubMed

    Zhao, Lu; Xu, Jianhua; Liang, Fang; Li, Ao; Zhang, Yong; Sun, Jue

    2015-01-01

    Metastasis to the liver is a main factor in colorectal cancer mortality. Previous studies suggest that chronic psychological stress is important in cancer progression, but its effect on liver metastasis has not been investigated. To address this, we established a liver metastasis model in BALB/c nude mice to investigate the role of chronic stress in liver metastasis. Our data suggest that chronic stress elevates catecholamine levels and promotes liver metastasis. Chronic stress was also associated with increased tumor associated macrophages infiltration into the primary tumor and increased the expression of metastatic genes. Interestingly, β-blocker treatment reversed the effects of chronic stress on liver metastasis. Our results suggest the β-adrenergic signaling pathway is involved in regulating colorectal cancer progression and liver metastasis. Additionally, we submit that adjunctive therapy with a β-blocker may complement existing colorectal cancer therapies. PMID:26444281

  17. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis

    PubMed Central

    Nielsen, Sebastian R; Quaranta, Valeria; Linford, Andrea; Emeagi, Perpetua; Rainer, Carolyn; Santos, Almudena; Ireland, Lucy; Sakai, Takao; Sakai, Keiko; Kim, Yong-Sam; Engle, Dannielle; Campbell, Fiona; Palmer, Daniel; Ko, Jeong Heon; Tuveson, David A.; Hirsch, Emilio; Mielgo, Ainhoa; Schmid, Michael C

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. Macrophages enhance metastasis in many cancer types, however, the role of macrophages in PDAC liver metastasis remains poorly understood. Here we found that PDAC liver metastasis critically depends on the early recruitment of granulin secreting inflammatory monocytes to the liver. Mechanistically, we demonstrate that granulin secretion by metastasis associated macrophages (MAMs) activates resident hepatic stellate cells (hStCs) into myofibroblasts that secrete periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment or genetic depletion of granulin reduced hStCs activation and liver metastasis. Interestingly, we found that circulating monocytes and hepatic MAMs in PDAC patients express high levels of granulin. These findings suggest that recruitment of granulin expressing inflammatory monocytes plays a key role in PDAC metastasis and may serve as a potential therapeutic target for PDAC liver metastasis. PMID:27088855

  18. A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4.

    PubMed

    Hansen, M T; Forst, B; Cremers, N; Quagliata, L; Ambartsumian, N; Grum-Schwensen, B; Klingelhöfer, J; Abdul-Al, A; Herrmann, P; Osterland, M; Stein, U; Nielsen, G H; Scherer, P E; Lukanidin, E; Sleeman, J P; Grigorian, M

    2015-01-22

    S100A4 is implicated in metastasis and chronic inflammation, but its function remains uncertain. Here we establish an S100A4-dependent link between inflammation and metastatic tumor progression. We found that the acute-phase response proteins serum amyloid A (SAA) 1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-κB signaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cell expressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrix metalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulate their own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, they strongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of human and mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins and cytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 or SAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massive infiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samples from colorectal carcinoma patients significantly correlated with reduced overall survival. These data show that SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a link between inflammation and tumor progression. PMID:24469032

  19. Primary mediastinal choriocarcinoma with brain metastasis in a female patient.

    PubMed

    Kuno, I; Matsumoto, Y; Kasai, M; Fukuda, T; Hashiguchi, Y; Ichimura, T; Yasui, T; Sumi, T

    2016-01-01

    Nongestational choriocarcinoma is very rare and carries a poor prognosis in female patients. In this report, the authors present a case of nongestational choriocarcinoma with brain metastasis in a female. A 58-year-old female with intermittent back pain was referred to a private hospital. On examination, a mediastinal tumor and a pancreatic tumor were detected. Endoscopic ultrasound-guided fine needle aspiration biopsy of the tumor was performed for histological evaluation. Pathological diagnosis was difficult because only a small amount of tissue was collected. Head MRI showed multiple metastatic tumors in the brain. The patient was diagnosed with primary mediastinal choriocarcinoma with brain metastasis. She was treated with one course of an etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine regimen, but her general condition gradually deteriorated, and she died on day 41. Nongestational choriocarcinoma is drug resistant, whereas gestational choriocarcinoma has better chemotherapeutic sensitivity. PMID:27172760

  20. A Case of Spine Origin Chondroblastoma Metastasis to Lung

    PubMed Central

    Sohn, Se Hoon; Koh, Sung Aee; Kim, Dong Geun; Park, Sung Woo; Lee, Kyung Hee; Kim, Min Kyoung; Choi, Jun Hyuk

    2009-01-01

    Chondroblastoma is a rare benign cartilaginous neoplasm that accounts for approximately 1% of all bone tumors and characteristically arises in the epiphysis of a long bone, particularly the humerus, tibia, and femur. Chondroblastoma can affect people of all ages. It is, however, most common in children and young adults between the ages of 10 and 20 years. Although most chondroblastomas are cured by limited surgical procedures, occasional lesions behave more aggressively and may even metastasis. In this case a young man with pulmonary metastatic chondroblastoma on spine is presented. Unlike previously published examples of metastatic chondroblastoma, these metastasis developed before any operative manipulation of the primary tumor. And primary tumor site was also unusual. The histologic characteristics of the primary, metastatic tumors were those of a conventional chondroblastoma. PMID:20057972

  1. Hemorrhagic collision metastasis in a cerebral arteriovenous malformation

    PubMed Central

    Sundarakumar, Dinesh K; Marshall, Desiree A; Keene, C Dirk; Rockhill, Jason K; Margolin, Kim A; Kim, Louis J

    2014-01-01

    A 26-year-old patient with recurrent choriocarcinoma of the testis presented with headache and progressive left homonymous hemianopsia. On initial MRI a grade 4 arteriovenous malformation (AVM) was identified in the right occipital lobe, which was further characterized by catheter angiography. Continued worsening of the headache in the following days prompted a follow-up MRI, which revealed a new T2 hypointense nodule and adjacent vasogenic edema in the periphery of the AVM. A follow-up MRI showed a marked increase in the size of the nodule with intrinsic enhancement and worsening perilesional edema. Based on the imaging evolution, the nodule was diagnosed as a metastasis and the patient was started on chemotherapy and radiotherapy. One week after the MRI he developed a sudden hemorrhage within the mass requiring decompression craniectomy and resection of both AVM and tumor. The histopathology of the resected mass confirmed the diagnosis of choriocarcinoma metastasis to the AVM. PMID:25239982

  2. Tumor heterogeneity and the biology of cancer invasion and metastasis.

    PubMed

    Fidler, I J

    1978-09-01

    The development of a metastasis is dependent on an interplay between host factors and intrinsic characteristics of malignant tumor cells. The process of metastasis is highly selective, and the metastatic lesion represents the end point of many destructive events that only a few cells can survive. Neoplasms, which are predominantly heterogeneous, contain a variety of subpopulations of cells with differing metastatic potential. Furthermore, metastatic cell variants have been shown to preexist in murine neoplasms of old and recent origin. The possible existence of highly metastatic variant cells within a primary tumor suggests that we no longer should consider a neoplasm to be a uniform entity. Efforts to design effective therapeutic agents and procedures against malignant tumors should be directed toward the few but fatal metastatic subpopulations of cells.

  3. Distant metastasis from benign solitary fibrous tumor of the kidney.

    PubMed

    Sasaki, Hideo; Kurihara, Tsuyoshi; Katsuoka, Yuichi; Nakano, Toru; Yoshioka, Maki; Miyano, Satetsu; Sato, Yuichi; Uejima, Iwao; Hoshikawa, Masahiro; Takagi, Masayuki; Chikaraishi, Tatsuya

    2013-01-01

    Solitary fibrous tumor (SFT) rarely occurs in the kidneys, and only one reported case of renal SFT has shown distant metastasis. We report the second case of renal SFT exhibiting distant metastasis. A 48-year-old man was referred to our hospital because of a right renal mass. An abdominal CT scan detected a large renal tumor, which was suspected to be a renal cell carcinoma. Right radical nephrectomy was performed, and the tumor was found to measure 28 × 18 × 10 cm. The pathological diagnosis was benign solitary fibrous tumor of the kidney. Eight years after the operation, lung and liver metastases developed. Pulmonary segmentectomy and partial hepatectomy were performed. The pathological diagnoses of these resected tissue specimens were compatible with benign SFT.

  4. [Metastasis and progression mechanisms of soft tissue tumors].

    PubMed

    Steinestel, K; Wardelmann, E

    2015-11-01

    Invasion and metastatic dissemination of tumor cells defines prognosis not only in patients with epithelial, but also mesenchymal neoplasms. Early and clinically inapparent micrometastases occur in many patients, and the risk for metastasis correlates with the tumor subtype and histologic tumor grade. In recent years and analogous to the situation in epithelial tumors, mechanisms of tumor cell dissemination in soft tissue tumors have been increasingly understood, and it has been shown that reorganization of the actin cytoskeleton plays a key role in these processes. This review summarizes current knowledge on the mechanisms of progression and metastasis of soft tissue tumors and points out possible targets for novel anti-invasive and anti-metastatic therapies. PMID:26324521

  5. Rectal metastasis from Breast cancer: A rare entity

    PubMed Central

    Ng, Cho Ee; Wright, Lucie; Pieri, Andrew; Belhasan, Anas; Fasih, Tarannum

    2015-01-01

    Introduction Breast cancer metastases occurs in around 50% of all presentation. It is the second most common type of cancer to metastasise to the GI tract but this only occurs in less than 1% of cases. Presentation of case We report a case that underwent treatment for invasive lobular cancer (ILC) of the breast and 5 years later was found to have rectal and peritoneal metastasis. She is currently receiving palliative management including chemotherapy in the form of weekly Paclitaxel (Taxol®) and stenting to relieve obstruction. Conclusion There should be high clinical suspicion of bowel metastasis in patients presenting with positive faecal occult blood with or without bowel symptoms even if the incidence is less <1% of metastases, particularly in cases where the initial breast tumour was large, with positive axillary nodes. PMID:26188979

  6. Methods to Study Metastasis in Genetically Modified Mice.

    PubMed

    Kabeer, Farhia; Beverly, Levi J; Darrasse-Jèze, Guillaume; Podsypanina, Katrina

    2016-02-01

    Metastasis is often modeled by xenotransplantation of cell lines in immunodeficient mice. A wealth of information about tumor cell behavior in the new environment is obtained from these efforts. Yet by design, this approach is "tumor-centric," as it focuses on cell-autonomous determinants of human tumor dissemination in mouse tissues, in effect using the animal body as a sophisticated "Petri dish" providing nutrients and support for tumor growth. Transgenic or gene knockout mouse models of cancer allow the study of tumor spread as a systemic disease and offer a complimentary approach for studying the natural history of cancer. This introduction is aimed at describing the overall methodological approach to studying metastasis in genetically modified mice, with a particular focus on using animals with regulated expression of potent human oncogenes in the breast. PMID:26832689

  7. Differentially expressed microRNAs in colorectal cancer metastasis

    PubMed Central

    Abba, Mohammed; Benner, Axel; Patil, Nitin; Heil, Oliver; Allgayer, Heike

    2015-01-01

    Tumor metastasis continues to be the most significant contributor to cancer related mortality, and although several studies have examined expression profiles emanating from patients with metastatic disease, very little information is available about signatures that differentiate metastatic lesions from primary tumors and associated normal tissues, largely because such matched tissue sample series are rare. This study was specifically designed to identify the metastasis relevant microRNAs in colorectal cancer and characterize microRNAs that modulate the metastatic phenotype. Here we describe in detail how the data, deposited in the Gene Expression Omnibus (GEO) with the accession number GSE54088, was generated including the basic analysis as contained in the manuscript published in Cancer Research with the PMID 26069251. PMID:26697326

  8. Systems microscopy approaches to understand cancer cell migration and metastasis

    PubMed Central

    Le Dévédec, Sylvia E.; Yan, Kuan; de Bont, Hans; Ghotra, Veerander; Truong, Hoa; Danen, Erik H.; Verbeek, Fons

    2010-01-01

    Cell migration is essential in a number of processes, including wound healing, angiogenesis and cancer metastasis. Especially, invasion of cancer cells in the surrounding tissue is a crucial step that requires increased cell motility. Cell migration is a well-orchestrated process that involves the continuous formation and disassembly of matrix adhesions. Those structural anchor points interact with the extra-cellular matrix and also participate in adhesion-dependent signalling. Although these processes are essential for cancer metastasis, little is known about the molecular mechanisms that regulate adhesion dynamics during tumour cell migration. In this review, we provide an overview of recent advanced imaging strategies together with quantitative image analysis that can be implemented to understand the dynamics of matrix adhesions and its molecular components in relation to tumour cell migration. This dynamic cell imaging together with multiparametric image analysis will help in understanding the molecular mechanisms that define cancer cell migration. PMID:20556632

  9. Cutaneous pancreatic metastasis: a case report and review of literature.

    PubMed

    Hafez, H Z Abdel

    2008-01-01

    Pancreatic cancer is one of the most dangerous human cancers and will continue to be a major unsolved health problem as we enter the 21(st) century. This is the case despite advances in imaging technology and surgical management. Indeed, 80% to 90% of pancreatic cancers are diagnosed either at the locally advanced or metastatic stage. Cutaneous metastases originating from pancreatic cancer are relatively rare. The most common site of cutaneous metastasis is the umbilicus, and this is known as the Sister Joseph's nodule. Very few patients have been reported with cutaneous lesions disclosing a pancreatic carcinoma at sites other than the umbilical area. To the best of our knowledge, there have been no previous reports on cutaneous pancreatic metastasis in Egypt. This is a report on a patient with cutaneous pancreatic metastases at the neck and review of reported non-umbilical cutaneous metastases from pancreatic carcinoma in the literatures.

  10. Cutaneous pancreatic metastasis: a case report and review of literature.

    PubMed

    Hafez, Hza

    2007-01-01

    Pancreatic cancer is one of the most lethal human cancers and continues to be a major unsolved health problem as we enter the 21st century. This is the case despite advances in imaging technology and surgical management. Indeed, 80-90% of pancreatic cancers are diagnosed either at the locally advanced stage or metastatic stage. Cutaneous metastases originating from pancreatic cancer are relatively rare. The most common site of cutaneous metastasis is the umbilicus, and it is known as the Sister Joseph's nodule. Very few patients have been reported with cutaneous lesions disclosing pancreatic carcinoma at sites other than the umbilical area. To our knowledge, there were no previous reports on cutaneous pancreatic metastasis in Egypt. This is a report of a patient with cutaneous pancreatic metastases at the neck, followed by a review of reported non-umbilical cutaneous metastases from pancreatic carcinoma in the literature.

  11. Hemorrhagic collision metastasis in a cerebral arteriovenous malformation.

    PubMed

    Sundarakumar, Dinesh K; Marshall, Desiree A; Keene, C Dirk; Rockhill, Jason K; Margolin, Kim A; Kim, Louis J

    2014-01-01

    A 26-year-old patient with recurrent choriocarcinoma of the testis presented with headache and progressive left homonymous hemianopsia. On initial MRI a grade 4 arteriovenous malformation (AVM) was identified in the right occipital lobe, which was further characterized by catheter angiography. Continued worsening of the headache in the following days prompted a follow-up MRI, which revealed a new T2 hypointense nodule and adjacent vasogenic edema in the periphery of the AVM. A follow-up MRI showed a marked increase in the size of the nodule with intrinsic enhancement and worsening perilesional edema. Based on the imaging evolution, the nodule was diagnosed as a metastasis and the patient was started on chemotherapy and radiotherapy. One week after the MRI he developed a sudden hemorrhage within the mass requiring decompression craniectomy and resection of both AVM and tumor. The histopathology of the resected mass confirmed the diagnosis of choriocarcinoma metastasis to the AVM. PMID:25239982

  12. Hemorrhagic collision metastasis in a cerebral arteriovenous malformation.

    PubMed

    Sundarakumar, Dinesh K; Marshall, Desiree A; Keene, C Dirk; Rockhill, Jason K; Margolin, Kim A; Kim, Louis J

    2015-10-01

    A 26-year-old patient with recurrent choriocarcinoma of the testis presented with headache and progressive left homonymous hemianopsia. On initial MRI a grade 4 arteriovenous malformation (AVM) was identified in the right occipital lobe, which was further characterized by catheter angiography. Continued worsening of the headache in the following days prompted a follow-up MRI, which revealed a new T2 hypointense nodule and adjacent vasogenic edema in the periphery of the AVM. A follow-up MRI showed a marked increase in the size of the nodule with intrinsic enhancement and worsening perilesional edema. Based on the imaging evolution, the nodule was diagnosed as a metastasis and the patient was started on chemotherapy and radiotherapy. One week after the MRI he developed a sudden hemorrhage within the mass requiring decompression craniectomy and resection of both AVM and tumor. The histopathology of the resected mass confirmed the diagnosis of choriocarcinoma metastasis to the AVM. PMID:25261441

  13. Abrogating Cholesterol Esterification Suppresses Growth and Metastasis of Pancreatic Cancer

    PubMed Central

    Li, Junjie; Gu, Dongsheng; Lee, Steve Seung-Young; Song, Bing; Bandyopadhyay, Shovik; Chen, Shaoxiong; Konieczny, Stephen F.; Ratliff, Timothy L.; Liu, Xiaoqi; Xie, Jingwu; Cheng, Ji-Xin

    2016-01-01

    Cancer cells are known to execute reprogramed metabolism of glucose, amino acids, and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By employing label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification. PMID:27132508

  14. Multiple Metastasis-Like Bone Lesions in Scintigraphic Imaging

    PubMed Central

    Zhang, Ying; Zhao, Chunlei; Liu, Hongbiao; Hou, Haifeng; Zhang, Hong

    2012-01-01

    Multiple benign osteolytic lesions are very hard to differentiate from disseminated bone metastasis. Whole-body bone scintigraphy (WBBS) with technetium-99m methylene diphosphonate (Tc-99m MDP) demonstrates multiple lesions with increased uptake in any bone involved. Even combined with medical history and multiple imaging results, such as MRI and CT, the clinical diagnosis of metastasis lesion remains as a challenge. These clinical characteristics are similar to multiple malignant bone metastases and therefore affect the following treatment procedures. In this paper, we analyzed multiple benign osteolytic lesions, like eosinophilic granuloma (EG), multiple myeloma (MM), disseminated tuberculosis, fibrous dysplasia, or enchondroma, occurring in our daily clinical work and concluded that additional attention should be paid before giving the diagnosis of multiple bone metastases. PMID:22505821

  15. Targeting microRNAs to withstand cancer metastasis.

    PubMed

    Profumo, Valentina; Doldi, Valentina; Gandellini, Paolo; Zaffaroni, Nadia

    2015-01-01

    MicroRNAs are endogenous, regulatory, noncoding small RNAs shown to play a key role in controlling gene expression, mainly at the posttranscriptional level. Several lines of evidence highlighted the importance of selected microRNAs as essential actors of cancer initiation events, tumor progression towards malignancy, and ultimately metastasis. By acting as either prometastatic or antimetastatic factors, microRNAs may represent novel targets or tools to withstand cancer progression. This chapter summarizes the available strategies to manipulate the expression of metastasis-related microRNAs, either by mimicking or inhibiting them, in cell systems and in vivo models. In addition, we provide a broad overview of conceptual and technological issues that need to be addressed before microRNAs might be exploited in the clinical setting for the prevention and treatment of the metastatic disease.

  16. MTBP inhibits migration and metastasis of hepatocellular carcinoma.

    PubMed

    Bi, Qian; Ranjan, Atul; Fan, Rui; Agarwal, Neeraj; Welch, Danny R; Weinman, Steven A; Ding, Jie; Iwakuma, Tomoo

    2015-04-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with increasing incidence. Despite curative surgical resection and advanced chemotherapy, its survival rate remains low. The presence of microvascular invasion and occult metastasis is one of the major causes for this poor outcome. MDM2 Binding Protein (MTBP) has been implicated in the suppression of cell migration and cancer metastasis. However, clinical significance of MTBP, particularly in human cancer, is poorly understood. Specifically, clinical relevance of MTBP in human HCC has never been investigated. Here we demonstrated that expression of MTBP was significantly reduced in human HCC tissues compared to adjacent non-tumor tissues. MTBP expression was negatively correlated with capsular/vascular invasion and lymph node metastasis. Overexpression of MTBP resulted in the suppression of the migratory and metastatic potential of HCC cells, while its downregulation increased the migration. Consistent with the previous report, MTBP endogenously bound to alpha-actinin 4 (ACTN4) and suppressed ACTN4-mediated cell migration in multiple HCC cell lines. However, MTBP also inhibited migratory potential of PLC/PRF/5 HCC cells whose migration was not altered by manipulation of ACTN4 expression. These results suggest that mechanisms behind MTBP-mediated migration suppression may not be limited to the pathway involving ACTN4 in certain cellular contexts. Additionally, as a potential mechanism for reduced MTBP expression in tumors, we found that MTBP expression was increased following the treatment with histone deacetylase inhibitors (HDIs). Our study, for the first time, provides clinical relevance of MTBP in the suppression of HCC metastasis.

  17. Postoperative recurrence of papillary thyroid carcinoma with lymph node metastasis

    PubMed Central

    Liu, Feng‐Hsuan; Kuo, Sheng‐Fong; Hsueh, Chuen; Chao, Tzu‐Chieh

    2015-01-01

    Background and Objectives : The purpose of this study was to retrospectively analyze the features of patients with papillary thyroid carcinoma (PTC) presenting with neck lymph node (LN) metastasis. Methods : The study enrolled 909 patients with PTC who had undergone total thyroidectomy. After a median follow‐up of 14.6 years, 73 (8.0%) patients died of thyroid cancer. A total of 536 patients had the tumor confined to the thyroid (intra‐thyroid), 111 had lymph node (LN) metastasis, 225 showed soft tissue invasion, and 37 had distant metastasis. Results : Compared with the intra‐thyroid group, the group with LN metastases showed larger tumor size, higher postoperative thyroglobulin levels, advanced TNM stage, higher recurrence rates (5.2% vs. 31.5%), and higher disease‐specific mortality (1.3% vs. 12.6%). Of the 111 patients with PTC and LN metastases, 35 (31.5%) were diagnosed with recurrence during a mean follow‐up period of 16.9 ± 0.6 years. Among the 35 patients with recurrent PTC, 14 (40.0%) died of thyroid cancer. The mortality group was characterized by older, mostly male patients who presented with larger initial tumor size compared with survivors. Conclusions : In patients with PTC, the rates of recurrence and cancer mortality were higher in the group with LN metastasis than that in the intra‐thyroid tumor group. J. Surg. Oncol. 2015 111:149–154. © 2015 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals, Inc. PMID:26175314

  18. Massive granular cell ameloblastoma with metastasis: report of a case.

    PubMed

    Cranin, A N; Bennett, J; Solomon, M; Quarcoo, S

    1987-09-01

    The case of a woman with a massive recurrent anterior mandibular ameloblastoma of 45 years' duration that showed metastasis is presented. The aggressive nature of the tumor, its management, and the eventual outcome are discussed. Ameloblastomas, particularly after their first recurrence, must be viewed as potentially life-threatening lesions. Adequate resection early in the onset of such tumors may result in more successful and predictable results. PMID:3476703

  19. MTBP inhibits migration and metastasis of hepatocellular carcinoma.

    PubMed

    Bi, Qian; Ranjan, Atul; Fan, Rui; Agarwal, Neeraj; Welch, Danny R; Weinman, Steven A; Ding, Jie; Iwakuma, Tomoo

    2015-04-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with increasing incidence. Despite curative surgical resection and advanced chemotherapy, its survival rate remains low. The presence of microvascular invasion and occult metastasis is one of the major causes for this poor outcome. MDM2 Binding Protein (MTBP) has been implicated in the suppression of cell migration and cancer metastasis. However, clinical significance of MTBP, particularly in human cancer, is poorly understood. Specifically, clinical relevance of MTBP in human HCC has never been investigated. Here we demonstrated that expression of MTBP was significantly reduced in human HCC tissues compared to adjacent non-tumor tissues. MTBP expression was negatively correlated with capsular/vascular invasion and lymph node metastasis. Overexpression of MTBP resulted in the suppression of the migratory and metastatic potential of HCC cells, while its downregulation increased the migration. Consistent with the previous report, MTBP endogenously bound to alpha-actinin 4 (ACTN4) and suppressed ACTN4-mediated cell migration in multiple HCC cell lines. However, MTBP also inhibited migratory potential of PLC/PRF/5 HCC cells whose migration was not altered by manipulation of ACTN4 expression. These results suggest that mechanisms behind MTBP-mediated migration suppression may not be limited to the pathway involving ACTN4 in certain cellular contexts. Additionally, as a potential mechanism for reduced MTBP expression in tumors, we found that MTBP expression was increased following the treatment with histone deacetylase inhibitors (HDIs). Our study, for the first time, provides clinical relevance of MTBP in the suppression of HCC metastasis. PMID:25759210

  20. Liver metastasis of meningeal hemangiopericytoma: a study of 5 cases

    PubMed Central

    Lo, Regina C.; Suriawinata, Arief A.; Rubin, Brian P.

    2016-01-01

    Mesenchymal tumors in the liver, whether primary or metastatic, are rare. Meningeal hemangiopericytoma (HPC) is characteristically associated with delayed metastasis and the liver is one of the most common sites. Despite its consistent histological features, a pathological diagnosis of HPC in the liver is sometimes not straightforward due to its rarity and usually remote medical history of the primary meningeal tumor. In this report, the clinicopathological features of 5 cases of metastatic HPC to the liver were reviewed and described. PMID:27044772

  1. Isolated metachronous splenic metastasis from synchronous colon cancer

    PubMed Central

    Gencosmanoglu, Rasim; Aker, Fugen; Kir, Gozde; Tozun, Nurdan

    2006-01-01

    Background Isolated splenic metastases from colorectal cancer are very rare and there are only 13 cases reported in the English literature so far. Most cases are asymptomatic and the diagnosis is usually made by imaging studies during the evaluation of rising CEA level postoperatively. Case presentation A 76-year-old man underwent an extended left hemicolectomy for synchronous colon cancers located at the left flexure and the sigmoid colon. The tumors were staged as IIIC (T3N2M0) clinically and the patient received adjuvant chemotherapy. During the first year follow-up period, the patient remained asymptomatic with normal levels of laboratory tests including CEA measurement. However, a gradually rising CEA level after the 14th postoperative month necessitated further imaging studies including computed tomography of the abdomen which revealed a mass in the spleen that was subsequently confirmed by 18FDG- PET scanning to be an isolated metastasis. The patient underwent splenectomy 17 months after his previous cancer surgery. Histological diagnosis confirmed a metastatic adenocarcinoma with no capsule invasion. After an uneventful postoperative period, the patient has been symptom-free during the one-year of follow-up with normal blood CEA levels, although he did not accept to receive any further adjuvant therapy. To the best of our knowledge, this 14th case of isolated splenic metastasis from colorectal carcinoma is also the first reported case of splenic metastasis demonstrated preoperatively by 18FDG PET-CT fusion scanning which revealed its solitary nature as well. Conclusion Isolated splenic metastasis is a rare finding in the follow-up of colorectal cancer patients and long-term survival can be achieved with splenectomy. PMID:16824207

  2. Complexity and Dynamic Heterogeneity of the Process of Cancer Metastasis

    NASA Astrophysics Data System (ADS)

    Chambers, Ann

    2010-03-01

    Cancer metastasis -- the spread of cancer from a primary tumor to distant parts of the body -- is responsible for most cancer deaths. If cancer is detected early, before it has spread, it can often be treated with local therapies like surgery and radiation. If cancer is detected after it has already spread, it is much harder to treat successfully. Cancer cells may be distributed to many organs, may be present as tiny micrometastases that are hard to detect, and cancer cells can be in a dormant state that may be resistant to treatment that is directed against actively dividing cells. A better understanding of the process of metastasis thus is needed in order to improve survival from cancer. Cancer is not a static disease, but one that can undergo stepwise evolution and progression from early, treatable cancer to aggressive cancer that is harder to treat. Furthermore, cancers are made up of many cells, and there is considerable heterogeneity among the cells in a tumor. Thus, cancer is ``plastic,'' with heterogeneity among cancer cells and changes over time. Understanding this ``dynamic heterogeneity'' has proven to be difficult. Input from physical sciences disciplines may help to shed light on this complex aspect of cancer biology. Here the process of cancer metastasis will be discussed, and experimental models for imaging the process described. The concept of ``dynamic heterogeneity'' of the metastatic process will be discussed, and some of the questions that need to be addressed for better understanding of metastasis will be outlined. An evolving dialogue between cancer biologists and physical scientists may lead to new ways of studying and understanding this lethal aspect of cancer.

  3. Ubc9 promotes invasion and metastasis of lung cancer cells.

    PubMed

    Li, Hui; Niu, Huiyan; Peng, Yang; Wang, Jiahe; He, Ping

    2013-04-01

    Lung cancer is the leading cause of cancer-related mortality worldwide. The mortality is high mainly due to the lack of known effective screening procedures; there is a high tendency for early spread and systemic therapies do not cure metastatic disease. Thus, it is important to investigate the molecular mechanism(s) of lung cancer development and, specifically, to identify an effective method by which to inhibit the invasion and metastasis of lung cancer. Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays a key role in tumorigenesis. Whether Ubc9 is involved in the invasion and metastasis of lung cancer remains unknown. Herein, we report that Ubc9 exhibits an important role in lung cancer invasion and metastasis. We first investigated the biological effect of Ubc9 on lung cancer by cloning the Ubc9 gene into a eukaryotic expression plasmid and stably expressing it in the human small cell lung cancer cell line NCI-H446 in order to observe any biological changes. We further analyzed the effect of Ubc9 in an in vivo experiment, injecting NCI-H446 cells stably overexpressing Ubc9 into nude mice and analyzing their metastatic ability. Our results demonstrated that Ubc9 is expressed at higher levels in primary lung cancer tissue and metastatic nodules as compared to premalignant and/or normal tissue. Furthermore, we demonstrated that upregulation of Ubc9 expression promotes migration and invasion. Ubc9 likely plays an important role in cancer progression by promoting invasion and metastasis in lung cancer. PMID:23381475

  4. Intra Luminal Metastasis to Duodenum: A Histological Surprise

    PubMed Central

    Aroul, Tirou; Kuppusamy, Sasikumar; Gunashekaran, Vijay

    2016-01-01

    Carcinoma cervix is one of the most common malignancies seen in women worldwide and more so in the Indian subcontinent. Carcinoma cervix is known for its orderly lymphatic spread. Skip metastasis or intraluminal metastasis is not a frequent occurrence. A 50-year-old diabetic and hypertensive female patient who was diagnosed to have carcinoma cervix (stage II A 2) Grade II to III and post radiotherapy (3 years back) presented to the surgical outpatient with dyspeptic symptoms and vague abdominal pain. On examination she was found to have a 1x1cm hard, fixed, left supraclavicular node and a palpable liver. Ultrasound abdomen revealed multiple retro peritoneal lymphadenopathy and Contrast Enhanced Computerised Tomography (CECT) abdomen revealed secondary deposits in the pancreatico-duodenal groove infiltrating the duodenal C-loop and pancreatic head, with multiple retroperitoneal nodes with necrosis. Fine needle Aspiration Cytology (FNAC) from left supraclavicular node revealed metastatic squamous cell carcinoma. Oesophagogastroduodenoscopy showed 2 sessile lesions in the anterior wall of duodenum with mucosa stretched and central umbilication with almost complete luminal obstruction. Biopsy from the duodenal lesion also turned out positive for metastatic squamous cell carcinoma. Gynaecological examination was negative for any local recurrence. Patient was managed symptomatically for dyspepsia and is currently undergoing chemotherapy. She is at present on regular follow-up and is asymptomatic for the bowel metastasis. Given the frequency of cancer cervix and the rarity of intra luminal metastasis, this case report serves to reiterate the fact that the abdomen is truly a pandora’s box. PMID:27790514

  5. Integrated Genomic and Epigenomic Analysis of Breast Cancer Brain Metastasis

    PubMed Central

    Salhia, Bodour; Kiefer, Jeff; Ross, Julianna T. D.; Metapally, Raghu; Martinez, Rae Anne; Johnson, Kyle N.; DiPerna, Danielle M.; Paquette, Kimberly M.; Jung, Sungwon; Nasser, Sara; Wallstrom, Garrick; Tembe, Waibhav; Baker, Angela; Carpten, John; Resau, Jim; Ryken, Timothy; Sibenaller, Zita; Petricoin, Emanuel F.; Liotta, Lance A.; Ramanathan, Ramesh K.; Berens, Michael E.; Tran, Nhan L.

    2014-01-01

    The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies. PMID:24489661

  6. Outcomes with cytoreductive surgery and HIPEC for peritoneal metastasis.

    PubMed

    Ahmed, Shuja; Stewart, John H; Shen, Perry; Votanopoulos, Konstantinos I; Levine, Edward A

    2014-10-01

    Peritoneal metastasis (PM) has traditionally been approached with therapeutic nihilism. The evolution of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) over the last two decades, however, has caused a paradigm shift in treatment for PM. This modality is rapidly gaining acceptance as standard of care for PM from various cancers. This article reviews the current literature regarding the use of CRS/HIPEC for PM from the most common intra-abdominal malignancies. PMID:25164477

  7. Tissue invasion and metastasis: Molecular, biological and clinical perspectives.

    PubMed

    Jiang, W G; Sanders, A J; Katoh, M; Ungefroren, H; Gieseler, F; Prince, M; Thompson, S K; Zollo, M; Spano, D; Dhawan, P; Sliva, D; Subbarayan, P R; Sarkar, M; Honoki, K; Fujii, H; Georgakilas, A G; Amedei, A; Niccolai, E; Amin, A; Ashraf, S S; Ye, L; Helferich, W G; Yang, X; Boosani, C S; Guha, G; Ciriolo, M R; Aquilano, K; Chen, S; Azmi, A S; Keith, W N; Bilsland, A; Bhakta, D; Halicka, D; Nowsheen, S; Pantano, F; Santini, D

    2015-12-01

    Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-β), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks. PMID:25865774

  8. Augmentation of metastasis formation by thioglycollate-elicited macrophages.

    PubMed

    Gorelik, E; Wiltrout, R H; Brunda, M J; Holden, H T; Herberman, R B

    1982-05-15

    Inoculation of thioglycollate-elicited peritoneal exudate cells (PEC) into C57BL/6 mice reduced the rate of lung clearance of several intravenously (i.v.) injected murine tumor cells, and increased by up to 100-fold the number of artificially-induced metastatic lung nodules produced by the i.v. injection of B16 melanoma or Lewis lung carcinoma (3LL) tumor cells. Maximum effects were observed when PEC were injected either before, or shortly after, tumor cells. Modulation of lung clearance or metastasis formation was observed only with PEC and not with a variety of other cells, such as splenocytes, thymocytes P815 mastocytoma cells, or several macrophage-like cell lines (PU5-1.8 and IC-21). Lysates of PEC were as efficient in reducing lung clearance and augmenting metastasis formation as were intact viable PEC. Lysates of other cell types, including P815 and the macrophage-like cell lines, were unable to produce these effects. PEC populations, enriched for macrophages by adherence to plastic or by percoll density gradient sedimentation, also increased the number of B16-induced artificial metastasis, implicating the macrophage as the cell responsible for these observations. PMID:7095902

  9. Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

    PubMed Central

    Weissmann, Marina; Arvatz, Gil; Horowitz, Netanel; Feld, Sari; Naroditsky, Inna; Zhang, Yi; Ng, Mary; Hammond, Edward; Nevo, Eviatar; Vlodavsky, Israel; Ilan, Neta

    2016-01-01

    Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanase-neutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment. PMID:26729870

  10. A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma

    PubMed Central

    Luo, Zai-Li; Cheng, Shu-Qun; Shi, Jie; Zhang, Hui-Lu; Zhang, Cun-Zhen; Chen, Hai-Yang; Qiu, Bi-Jun; Tang, Liang; Hu, Cong-Li; Wang, Hong-Yang; Li, Zhong

    2015-01-01

    Merlin, which is encoded by the tumour suppressor gene Nf2, plays a crucial role in tumorigenesis and metastasis. However, little is known about the functional importance of Merlin splicing forms. In this study, we show that Merlin is present at low levels in human hepatocellular carcinoma (HCC), particularly in metastatic tumours, where it is associated with a poor prognosis. Surprisingly, a splicing variant of Merlin that lacks exons 2, 3 and 4 (Δ2–4Merlin) is amplified in HCC and portal vein tumour thrombus (PVTT) specimens and in the CSQT2 cell line derived from PVTT. Our studies show that Δ2–4Merlin interferes with the capacity of wild-type Merlin to bind β-catenin and ERM, and it is expressed in the cytoplasm rather than at the cell surface. Furthermore, Δ2–4Merlin overexpression increases the expression levels of β-catenin and stemness-related genes, induces the epithelium–mesenchymal-transition phenotype promoting cell migration in vitro and the formation of lung metastasis in vivo. Our results indicate that the Δ2–4Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis. PMID:26443326

  11. Automatic detection of rib metastasis in chest CT volume data

    NASA Astrophysics Data System (ADS)

    Shen, Hong; Ma, Limin; Kafer, Johannes; Naicich, David P.

    2007-03-01

    We describe a system for the automatic detection of rib metastasis in thoracic CT volume. Rib metastasis manifest itself as alterations of bone intensities or shapes, and the detection of these alterations is the goal of the algorithm. According to the tubular shape of the rib structures, the detection is based on the construction of 2D cross-sections planes along the full lengths of each of the individual ribs. The set of planes is orthogonal to the rib centerline, with is extracted by a previously developed segmentation algorithm based on recursive tracing. On each of these planes, a 2D image is constructed by interpolation in the region of interest around the centerline intersection and the plane. From this image the cortical and trabecular bones are segmented separately. The appearance and geometric properties of the bone structures are analyzed and categorized according to a set of rules that summarize the possible variation types due to metastasis. The features extracted from the cross-sections along a short length of the centerline are jointly evaluated. A positive detection is accepted only if the alteration of shape and appearance is consistent with a number of consecutive cross-sections along the rib centerline.

  12. Integrin activation controls metastasis in human breast cancer

    NASA Astrophysics Data System (ADS)

    Felding-Habermann, Brunhilde; O'Toole, Timothy E.; Smith, Jeffrey W.; Fransvea, Emilia; Ruggeri, Zaverio M.; Ginsberg, Mark H.; Hughes, Paul E.; Pampori, Nisar; Shattil, Sanford J.; Saven, Alan; Mueller, Barbara M.

    2001-02-01

    Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin v3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin v3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated αvβ3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant αvβ3D723R, but not αvβ3WT, in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin αvβ3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer.

  13. Breast cancer metastasis: a microRNA story.

    PubMed

    Negrini, Massimo; Calin, George Adrian

    2008-01-01

    MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions, which play an important role in breast cancer. Several studies have shown that miRNAs can act either as tumor suppressors or as oncogenes, and that measurement of miRNA expression in malignancies may have diagnostic and prognostic implications. This article highlights a series of three recent studies that prove the involvement of miRNAs in breast cancer metastases. The first proves that miR-10b indirectly activates the pro-metastatic gene RHOC by suppressing HOXD10, thus leading to tumor invasion and metastasis. The second proves that miR-373 and miR-520c can also promote tumor invasion and metastasis, at least in part by regulating the gene CD44. The third identifies miR-335, miR-206, and miR-126 as suppressors of breast cancer metastasis. Loss of miR-335 leads to the activation of SOX4 and TNC (encoding tenascin C), which are responsible for the acquisition of metastatic properties. Altogether, these remarkable findings are important for our understanding of malignant transformation in the breast and may have implications for the management of patients with advanced breast cancer. The use of miRNAs as anticancer therapeutic agents is promising, and such fine molecular studies certainly help in bringing miRNAs closer to clinical practice.

  14. Experimental Models to Study Lymphatic and Blood Vascular Metastasis

    PubMed Central

    Chen, Lu; Wu, Lily

    2011-01-01

    As a model system for the understanding of human cancer, the mouse has proved immensely valuable. Indeed, studies of mouse models have helped to define the nature of cancer as a genetic disease and demonstrated the causal role of genetic events found in tumors. As an experimental platform, they have provided critical insight into the process of tumor metastasis in the lymphovascular system. Once viewed with skepticism, mouse models are now an integral arm of basic and clinical cancer research. The use of a genetically tractable organism that shares organ systems and an immense degree of genetic similarity to humans provides a means to examine multiple features of human disease. Mouse models enable development and testing of new approaches to disease prevention and treatment, identification of early diagnostic markers and novel therapeutic targets, and an understanding of the in vivo biology and genetics of tumor initiation, promotion, progression, and metastasis. This review summarizes recent mouse models for lymphangiogenesis and the process of lymphovascular metastasis, focusing on the use of the cornea as an experimental platform for lymphangiogenesis in inflammation and immunity, and on the use of molecular and viral vector mediated imaging and to identify and monitor lymph node metastases of prostate cancer. PMID:21480239

  15. Atrial natriuretic peptide prevents cancer metastasis through vascular endothelial cells

    PubMed Central

    Nojiri, Takashi; Hosoda, Hiroshi; Tokudome, Takeshi; Miura, Koichi; Ishikane, Shin; Otani, Kentaro; Kishimoto, Ichiro; Shintani, Yasushi; Inoue, Masayoshi; Kimura, Toru; Sawabata, Noriyoshi; Minami, Masato; Nakagiri, Tomoyuki; Funaki, Soichiro; Takeuchi, Yukiyasu; Maeda, Hajime; Kidoya, Hiroyasu; Kiyonari, Hiroshi; Shioi, Go; Arai, Yuji; Hasegawa, Takeshi; Takakura, Nobuyuki; Hori, Megumi; Ohno, Yuko; Miyazato, Mikiya; Mochizuki, Naoki; Okumura, Meinoshin; Kangawa, Kenji

    2015-01-01

    Most patients suffering from cancer die of metastatic disease. Surgical removal of solid tumors is performed as an initial attempt to cure patients; however, surgery is often accompanied with trauma, which can promote early recurrence by provoking detachment of tumor cells into the blood stream or inducing systemic inflammation or both. We have previously reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduces inflammatory response and has a prophylactic effect on postoperative cardiopulmonary complications in lung cancer surgery. Here we demonstrate that cancer recurrence after curative surgery was significantly lower in ANP-treated patients than in control patients (surgery alone). ANP is known to bind specifically to NPR1 [also called guanylyl cyclase-A (GC-A) receptor]. In mouse models, we found that metastasis of GC-A–nonexpressing tumor cells (i.e., B16 mouse melanoma cells) to the lung was increased in vascular endothelium-specific GC-A knockout mice and decreased in vascular endothelium-specific GC-A transgenic mice compared with control mice. We examined the effect of ANP on tumor metastasis in mice treated with lipopolysaccharide, which mimics systemic inflammation induced by surgical stress. ANP inhibited the adhesion of cancer cells to pulmonary arterial and micro-vascular endothelial cells by suppressing the E-selectin expression that is promoted by inflammation. These results suggest that ANP prevents cancer metastasis by inhibiting the adhesion of tumor cells to inflamed endothelial cells. PMID:25775533

  16. Tie2 Regulates Tumor Metastasis of Oral Squamous Cell Carcinomas

    PubMed Central

    Kitajima, Daisuke; Kasamatsu, Atsushi; Nakashima, Dai; Miyamoto, Isao; Kimura, Yasushi; Saito, Tomoaki; Suzuki, Takane; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-01-01

    The endothelial-specific receptor, tyrosine kinase with immunoglobulin-like loops and epidermal growth factor homology domains-2 (Tie2) is a member of the tyrosine kinase family and is ubiquitous in normal tissues; however, little is known about the mechanisms and roles of Tie2 in oral squamous cell carcinomas (OSCCs). In the current study, we investigated the expression status of Tie2 in OSCCs by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry and the functional mechanisms of Tie2 using its overexpressed OSCC (oeTie2) cells and Tie2 blocking by its antibody. We found that Tie2 expression was down-regulated significantly (p < 0.05) in OSCCs compared with normal counterparts in vitro and in vivo. Interestingly, oeTie2 cells showed higher cellular adhesion (p < 0.05) and lower cellular invasion (p < 0.05) compared with control cells; whereas there was similar cellular proliferation in both transfectants. Furthermore, cellular adhesion was inhibited and invasion was activated by Tie2 function-blocking antibody (p < 0.05), indicating that Tie2 directly regulates cellular adhesion and invasion. As expected, among the clinical variables analyzed, Tie2-positivity in patients with OSCC was correlated closely with negative lymph node metastasis. These results suggested for the first time that Tie2 plays an important role in tumor metastasis and may be a potential biomarker for OSCC metastasis. PMID:27053959

  17. Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.

    PubMed

    Sinkevicius, Kerstin W; Kriegel, Christina; Bellaria, Kelly J; Lee, Jaewon; Lau, Allison N; Leeman, Kristen T; Zhou, Pengcheng; Beede, Alexander M; Fillmore, Christine M; Caswell, Deborah; Barrios, Juliana; Wong, Kwok-Kin; Sholl, Lynette M; Schlaeger, Thorsten M; Bronson, Roderick T; Chirieac, Lucian R; Winslow, Monte M; Haigis, Marcia C; Kim, Carla F

    2014-07-15

    Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosin-related kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and in vivo. In an autochthonous lung adenocarcinoma model driven by activated oncogenic Kras and p53 loss, TrkB deficiency significantly reduced metastasis. Hypoxia-inducible factor-1 directly regulated TrkB expression, and, in turn, TrkB activated Akt signaling in metastatic lung cancer cells. Finally, TrkB expression was correlated with metastasis in patient samples, and TrkB was detected more often in tumors that did not have Kras or epidermal growth factor receptor mutations. These studies demonstrate that TrkB is an important therapeutic target in metastatic lung adenocarcinoma. PMID:24982195

  18. Bone Targeted Therapies for Bone Metastasis in Breast Cancer

    PubMed Central

    Razaq, Wajeeha

    2013-01-01

    Cancer metastasis to the bone develops commonly in patients with various malignancies, and is a major cause of morbidity and diminished quality of life in many affected patients. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to the bone metastasis. The tendency of cancer cells to metastasize to bone is probably the end result of many factors including vascular pathways, the highly vascular nature of the bone marrow (which increases the probability that cancer cells will be deposited in bone marrow capillaries), and molecular characteristics of the cancer cells that allow them to adapt to the bone marrow microenvironment. The goals of treating osseous metastases are manifold. Proper treatment can lead to significant improvements in pain control and function, and maintain skeletal integrity. The treatment plan requires a multidisciplinary approach. Widespread metastatic disease necessitates systemic therapy, while a localized problem is best managed with surgery, external beam radiotherapy, or both. Patients with bone metastasis can have prolonged survival, and proper management can have a significant impact on their quality of life. We will review the factors in this article that are promising molecular bone-targeted therapies or will be likely targets for future therapeutic intervention to restore bone remodeling and suppress tumor growth. PMID:26237142

  19. Imaging Cancer Angiogenesis and Metastasis in a Zebrafish Embryo Model.

    PubMed

    Tulotta, C; He, S; van der Ent, W; Chen, L; Groenewoud, A; Spaink, H P; Snaar-Jagalska, B E

    2016-01-01

    Tumor angiogenesis and metastasis are key steps of cancer progression. In vitro and animal model studies have contributed to partially elucidating the mechanisms involved in these processes and in developing therapies. Besides the improvements in fundamental research and the optimization of therapeutic regimes, cancer still remains a major health threatening condition and therefore the development of new models is needed. The zebrafish is a powerful tool to study tumor angiogenesis and metastasis, because it allows the visualization of fluorescently labelled tumor cells inducing vessel remodeling, disseminating and invading surrounding tissues in a whole transparent embryo. The embryo model has also been used to address the contribution of the tumor stroma in sustaining tumor angiogenesis and spreading. Simultaneously, new anti-angiogenic drugs and compounds affecting malignant cell survival and migration can be tested by simply adding the compound into the water of living embryos. Therefore the zebrafish model offers the opportunity to gain more knowledge on cancer angiogenesis and metastasis in vivo with the final aim of providing new translational insights into therapeutic approaches to help patients. PMID:27165357

  20. [A case of malignant melanoma metastasis to the mammary gland].

    PubMed

    Tanaka, Ryota; Kashiwagi, Shinichiro; Ishihara, Sae; Asano, Yuka; Noda, Satoru; Kawajiri, Hidemi; Takashima, Tsutomu; Onoda, Naoyoshi; Ohsawa, Masahiko; Hirakawa, Kosei

    2014-11-01

    Herein, we report a rare case of malignant melanoma metastasis to the mammary gland. A 76-year-old woman had a tumor resection performed for primary malignant melanoma of the epipharynx. The patient subsequently underwent local and lymph node recurrence, for which she received heavy ion radiotherapy and lymph node dissection, respectively. The patient was referred to our hospital for a problem with her right breast. Computed tomography and magnetic resonance imaging showed a mammary tumor and multiple subcutaneous tumors. A biopsy was performed, which proved positive for S100 and Melan A staining, and the diagnosis of malignant melanoma was confirmed. Partial mastectomy was performed; and S100, HMB45, and Melan A positivity was confirmed based on immunohistological findings. The diagnosis was malignant melanoma metastasis to the mammary gland. Malignant melanoma commonly metastasizes to the liver, mediastinum, mediastinal glands, lung, and brain; and metastasis to the mammary gland is rare. To our knowledge, only 2 cases have previously been reported in the Japanese literature.

  1. Honokiol targets mitochondria to halt cancer progression and metastasis.

    PubMed

    Pan, Jing; Lee, Yongik; Wang, Yian; You, Ming

    2016-06-01

    Cancer continues to be the leading cause of death worldwide. Plants have a long history of use in the treatment of cancer. Honokiol (HNK) is an important bioactive compound found in the bark of Magnolia tree, and has been shown to inhibit cancer growth and metastasis in many cell types in vitro and in animal models. Resistance to chemotherapy and radiotherapy is the major obstacle for cure of cancer. Combination of HNK with many traditional chemotherapeutic drugs as well as radiation sensitizes cancer cells to apoptotic death, suggesting that HNK not only directly inhibits primary cancers and metastasis, but also has potential to overcome drug resistance. Ultimately, this may mean that HNK could be combined with traditional chemotherapies administered at lower doses to significantly reduce toxicity, meanwhile enhance efficacy. As a natural compound, HNK is composed of polyphenols and has been described in many studies targeting multiple key cell signaling molecules. Mitochondria are the main hub for cellular energy production and play an important role in cell survival, and are the key target identified for HNK to mediate cancer cell death, survival, and metastasis. In this review, we have summarized different aspects of HNK's anti-cancer effects from recent accumulated literature, as well as the underlying molecular mechanisms. This review is primarily focused on the effects of HNK on epidermal growth factor receptor (EGFR) and signal transduction and activator of transcription 3 (STAT3) signaling, as well as the broader regulation of mitochondrial function and cancer cell metabolism. PMID:27276215

  2. Involvement of chemokine receptors in breast cancer metastasis

    NASA Astrophysics Data System (ADS)

    Müller, Anja; Homey, Bernhard; Soto, Hortensia; Ge, Nianfeng; Catron, Daniel; Buchanan, Matthew E.; McClanahan, Terri; Murphy, Erin; Yuan, Wei; Wagner, Stephan N.; Barrera, Jose Luis; Mohar, Alejandro; Verástegui, Emma; Zlotnik, Albert

    2001-03-01

    Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

  3. EGFR and HER2 signaling in breast cancer brain metastasis.

    PubMed

    Sirkisoon, Sherona R; Carpenter, Richard L; Rimkus, Tadas; Miller, Lance; Metheny-Barlow, Linda; Lo, Hui-Wen

    2016-01-01

    Breast cancer occurs in approximately 1 in 8 women and 1 in 37 women with breast cancer succumbed to the disease. Over the past decades, new diagnostic tools and treatments have substantially improved the prognosis of women with local diseases. However, women with metastatic disease still have a dismal prognosis without effective treatments. Among different molecular subtypes of breast cancer, the HER2-enriched and basal-like subtypes typically have higher rates of metastasis to the brain. Basal-like metastatic breast tumors frequently express EGFR. Consequently, HER2- and EGFR-targeted therapies are being used in the clinic and/or evaluated in clinical trials for treating breast cancer patients with brain metastases. In this review, we will first provide an overview of the HER2 and EGFR signaling pathways. The roles that EGFR and HER2 play in breast cancer metastasis to the brain will then be discussed. Finally, we will summarize the preclinical and clinical effects of EGFR- and HER2-targeted therapies on breast cancer metastasis.

  4. Non-coding RNAs in cancer brain metastasis.

    PubMed

    Wu, Kerui; Sharma, Sambad; Venkat, Suresh; Liu, Keqin; Zhou, Xiaobo; Watabe, Kounosuke

    2016-01-01

    More than 90% of cancer death is attributed to metastatic disease, and the brain is one of the major metastatic sites of melanoma, colon, renal, lung and breast cancers. Despite the recent advancement of targeted therapy for cancer, the incidence of brain metastasis is increasing. One reason is that most therapeutic drugs can't penetrate blood-brain-barrier and tumor cells find the brain as sanctuary site. In this review, we describe the pathophysiology of brain metastases to introduce the latest understandings of metastatic brain malignancies. This review also particularly focuses on non-coding RNAs and their roles in cancer brain metastasis. Furthermore, we discuss the roles of the extracellular vesicles as they are known to transport information between cells to initiate cancer cell-microenvironment communication. The potential clinical translation of non-coding RNAs as a tool for diagnosis and for treatment is also discussed in this review. At the end, the computational aspects of non-coding RNA detection, the sequence and structure calculation and epigenetic regulation of non-coding RNA in brain metastasis are discussed.

  5. Protocadherin-7 induces bone metastasis of breast cancer

    SciTech Connect

    Li, Ai-Min; Tian, Ai-Xian; Zhang, Rui-Xue; Ge, Jie; Sun, Xuan; Cao, Xu-Chen

    2013-07-05

    Highlights: •PCDH7 is overexpression in high bone metastatic MDA-MB-231 cells. •PCDH7 is up-regulation in bone metastatic breast cancer tissues. •Suppression of PCDH7 inhibits cell proliferation, migration, and invasion in vitro. •PCDH7 induces breast cancer bone metastasis in vivo. -- Abstract: Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bone metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer.

  6. The emerging role of RUNX3 in cancer metastasis (Review).

    PubMed

    Chen, Feifei; Liu, Xin; Bai, Jin; Pei, Dongsheng; Zheng, Junnian

    2016-03-01

    Metastasis remains the major driver of mortality in patients with cancer. The multistep metastatic process starts with the dissemination of tumor cells from a primary site and leading to secondary tumor development in an anatomically distant location. Although significant progress has been made in understanding the molecular characteristics of metastasis, many questions remain regarding the intracellular mechanisms governing transition through the various metastatic stages. The runt-related transcription factor 3 (RUNX3) is a downstream effector of the transforming growth factor-β (TGF-β) signaling pathway, and has critical roles in the regulation of cell death by apoptosis, and in angiogenesis, epithelial-to-mesenchymal transition (EMT), cell migration and invasion. RUNX3 functions as a bona fide initiator of carcinogenesis by linking the Wnt oncogenic and TGF-β tumor suppressive pathways. RUNX3 is frequently inactivated in human cancer cell lines and cancer samples by hemizygous deletion of the Runx3 gene, hypermethylation of the Runx3 promoter, or cytoplasmic sequestration of RUNX3 protein. Inactivation of RUNX3 makes it a putative tumor suppressor in human neoplasia. In the present review, we summarize the proposed roles of RUNX3 in metastasis and, when applicable, highlight the mechanism by which they function. PMID:26708741

  7. CD47 Promotes Tumor Invasion and Metastasis in Non-small Cell Lung Cancer

    PubMed Central

    Zhao, Hui; Wang, Jianxin; Kong, Xiaodan; Li, Encheng; Liu, Yuanbin; Du, Xiaohui; Kang, Zhijie; Tang, Ying; Kuang, Yanbin; Yang, Zhihui; Zhou, Youwen; Wang, Qi

    2016-01-01

    CD47 is overexpressed in many human cancers, its level positively correlates with tumor invasion and metastasis. However, it is largely unknown whether CD47 overexpression drives metastasis and how CD47 lead to tumor metastasis in non-small cell lung cancer (NSCLC). In this study, we analyzed NSCLC specimens and cell lines, and revealed that CD47 is expressed at a higher level than in tumor-free control samples. Furthermore, increased CD47 expression correlated with clinical staging, lymph node metastasis and distant metastasis. In order to understand the molecular mechanisms underlying CD47 functions, we applied both gain-of-function and loss-of-function approaches in cell lines. The siRNA-mediated downregulation of CD47 inhibited cell invasion and metastasis in vitro, while the overexpression of CD47 by plasmid transfection generated opposite effects. In vivo, CD47-specific shRNA significantly reduced tumor growth and metastasis. On the molecular level, the expression of CD47 correlated with that of Cdc42, both in cell lines and NSCLC specimens. The inhibition of Cdc42 attenuates the invasion and metastasis of CD47-overexpressing cells. These results indicate that Cdc42 is a downstream mediator of CD47-promoted metastasis. Our findings provide first evidence that CD47 is an adverse prognostic factor for disease progression and metastasis, and a promising therapeutic target for NSCLC. PMID:27411490

  8. Effects of incision and irradiation on regional lymph node metastasis in carcinoma of the hamster tongue

    SciTech Connect

    Ohtake, K.; Shingaki, S.; Nakajima, T. )

    1990-07-01

    The effects of incision and irradiation on regional lymph node metastasis in DMBA-induced squamous cell carcinomas of the hamster tongue are reported. Metastasis to the submandibular lymph nodes was confirmed histologically in 48.0% of the animals. The incidence of lymph node metastasis was significantly increased (65.9%) after repeated incisions of tongue carcinomas. Three gray whole-body irradiation also increased the rate of metastasis from 31.0% to 46.3%. Higher incidences of lymphatic vessel invasion after incision and concomitant lymph node metastasis in the lymphatic invasion-positive group indicated a stepwise relationship leading to an increase in lymph node metastasis after incision. Because of the high incidence of metastases and close resemblance to human carcinomas in the tumor cell deposition and establishment of metastatic foci, DMBA-induced tongue carcinoma with invasion may serve as an experimental model of human oral carcinomas.

  9. Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis.

    PubMed

    Batista, Silvia; Maniati, Eleni; Reynolds, Louise E; Tavora, Bernardo; Lees, Delphine M; Fernandez, Isabelle; Elia, George; Casanovas, Oriol; Lo Celso, Cristina; Hagemann, Thorsten; Hodivala-Dilke, Kairbaan

    2014-01-01

    Metastasis is the main cause of cancer-related death and thus understanding the molecular and cellular mechanisms underlying this process is critical. Here, our data demonstrate, contrary to established dogma, that loss of haematopoietic-derived focal adhesion kinase (FAK) is sufficient to enhance tumour metastasis. Using both experimental and spontaneous metastasis models, we show that genetic ablation of haematopoietic FAK does not affect primary tumour growth but enhances the incidence of metastasis significantly. At a molecular level, haematopoietic FAK deletion results in an increase in PU-1 levels and decrease in GATA-1 levels causing a shift of hematopoietic homeostasis towards a myeloid commitment. The subsequent increase in circulating granulocyte number, with an increase in serum CXCL12 and granulocyte CXCR4 levels, was required for augmented metastasis in mice lacking haematopoietic FAK. Overall our findings provide a mechanism by which haematopoietic FAK controls cancer metastasis. PMID:25270220

  10. Apoplexy in sellar metastasis: a case report and review of literature.

    PubMed

    Chhiber, Sarbjit Singh; Bhat, Abdul Rashid; Khan, Shoukat H; Wani, Mohd Afzal; Ramzan, Altaf U; Kirmani, Altaf R; Malik, Nayel K; Wani, Abrar A; Rather, Tanveer

    2011-01-01

    Apoplexy in sellar metastasis is very rare with only a few case reports in literature. A case of apoplexy in sellar metastasis from follicular thyroid carcinoma is reported and the literature is briefly reviewed. The patient presented with sudden onset headache and bi-lateral loss of vision following thyroidectomy in a case of follicular carcinoma thyroid with proven sellar metastasis. CT scan showed hyperdense blood in sellar mass suggestive of apoplexy in sellar metastasis. The patient underwent early trans-sphenoidal decompression. Apoplexy in sellar metastasis, although very rare, can be clinico-radiologically indistinguishable from pituitary apoplexy and should be especially considered in the differential diagnosis of patients with known primary neoplastic disease. In view of similar patho-physiological mechanism, sellar metastasis with apoplexy should be managed in a similar manner as pituitary apoplexy. PMID:21534208

  11. Epigenetic regulator RBP2 is critical for breast cancer progression and metastasis

    PubMed Central

    Cao, Jian; Liu, Zongzhi; Cheung, William K.C.; Zhao, Minghui; Chen, Sophia Y.; Chan, Siew Wee; Booth, Carmen J.; Nguyen, Don X.; Yan, Qin

    2014-01-01

    Summary Metastasis is a major clinical challenge for cancer treatment. Emerging evidence suggests that epigenetic aberrations contribute significantly to tumor formation and progression. However, the drivers and roles of such epigenetic changes in tumor metastasis are still poorly understood. Using bioinformatic analysis of human breast cancer gene expression datasets, we identified histone demethylase RBP2 as a putative mediator of metastatic progression. By using both human breast cancer cells and genetically engineered mice, we demonstrated that RBP2 is critical for breast cancer metastasis to the lung in multiple in vivo models. Mechanistically, RBP2 promotes metastasis as a pleiotropic positive regulator of many metastasis genes. In addition, RBP2 loss suppresses tumor formation in the MMTV-neu transgenic mice. These results suggest that therapeutically targeting RBP2 is a potential strategy to inhibit tumor progression and metastasis. PMID:24582965

  12. Ack1 overexpression promotes metastasis and indicates poor prognosis of hepatocellular carcinoma

    PubMed Central

    Chen, Guo-dong; Ou, Di-peng; Qiu, Xiao-xin; Zuo, Chao-hui; Yang, Lian-Yue

    2015-01-01

    Despite the substantial data supporting the oncogenic role of Ack1, the predictive value and biologic role of Ack1 in hepatocellular carcinoma (HCC) metastasis remains unknown. In this study, both correlations of Ack1 expression with prognosis of HCC, and the role of Ack1 in metastasis of HCC were investigated in vitro and in vivo. Our results showed that Ack1 was overexpressed in human HCC tissues and cell lines. High Ack1 expression was associated with HCC metastasis and determined as a significant and independent prognostic factor for HCC after liver resection. Ack1 promoted HCC invasion and metastasis in vitro and in vivo. Mechanistically, we confirmed that Ack1 enhanced invasion and metastasis of HCC via EMT by mediating AKT phosphorylation. In conclusion, our study shows Ack1 is a novel prognostic biomarker for HCC and promotes metastasis of HCC via EMT by activating AKT signaling. PMID:26536663

  13. [Renal cell carcinoma metastasis to the thyroid gland 15 years after nephrectomy].

    PubMed

    Mathiesen, Jes Sloth; Fleischer, Jens Geelmuyden; Godballe, Christian

    2015-01-26

    Renal cell carcinoma (RCC) metastasis to the thyroid gland is rare and can mimic primary thyroid carcinoma leading to diagnostic difficulties. We present a case of a 55-year-old female with RCC metastasis to the thyroid gland 15 years after nephrectomy. Diagnosis was made after total thyroidectomy. This case emphasizes the importance of considering metastasis in patients with increasing growth of the thyroid gland over a short period of time known with earlier RCC, even decades after nephrectomy. PMID:25612964

  14. Intracardiac metastasis from known cervical cancer: a case report and literature review.

    PubMed

    Byun, Seung Won; Park, Sung Taek; Ki, Eun Young; Song, Hyun; Hong, Suk Hee; Park, Jong Sup

    2013-05-23

    Cardiac metastasis from known cervical cancer is rare. Even through a routine check-up, this type of metastasis can present as pulmonary emboli. Suspicion of this diagnosis in an oncology patient with complicating pulmonary emboli but no evidence of deep vein thrombosis is important, especially in cervical cancer patients with extensive pelvic lymph node metastasis and vascular invasion of a primary tumor. Early recognition may aid in improving the prognosis. We present a case of intracardiac metastasis arising from a squamous carcinoma of the cervix in a patient with pulmonary tumor emboli and review other cases from the literature.

  15. Conus medullaris metastasis in breast cancer: report of a case and a review of the literature.

    PubMed

    Hsu, Kao-Chih; Li, Tsung-Ying; Chu, Heng-Yi; Chen, Liang-Cheng; Chang, Shin-Tsu; Wu, Yung-Tsan

    2013-08-01

    Intramedullary spinal cord metastasis is quite rare. This report presents the case of a female patient with metastasis of the conus medullaris from breast cancer, presenting with paraplegia and sphincter dysfunction. Bladder dysfunction improved after removal of the conus mass. This report is the seventh case of conus medullaris metastasis from breast cancer and the first review of clinical outcome, survival time and other data of all these 7 cases. This study also reviewed cases of intramedullary spinal cord metastasis arising from breast cancer in regions other than the conus medullaris in the literature. Longer survival time resulted from surgery in contrast to those without surgery in the latter group.

  16. EGFR-Mutated Breast Metastasis of Lung Adenocarcinoma: A Case Report.

    PubMed

    Dansin, Eric; Carnot, Aurélien; Servent, Véronique; Daussay, Dorothée; Robin, Yves-Marie; Surmei-Pintilie, Ecaterina; Lauridant, Géraldine; Descarpentries, Clothilde; Révillion, Françoise; Delattre, Claire

    2015-01-01

    Breast metastasis from other primary carcinoma is very rare and could be difficult to identify despite immunohistochemistry analysis. Breast metastasis from lung adenocarcinoma can mimic triple-negative breast cancer. Given the prognosis and therapeutic challenges, a correct diagnosis appears essential, and molecular biomarkers could be useful. We report the case of a 52-year-old woman with a breast mass initially diagnosed as primary breast cancer and secondarily attached to breast metastasis from an EGFR-mutated lung adenocarcinoma. The same activating EGFR mutations were identified in both the primary lung carcinoma and the breast metastasis.

  17. [Complete remission of brain metastasis of bladder cancer treated by M-VAC therapy].

    PubMed

    Nakagawa, S; Nakao, M; Toyoda, K; Nukui, M; Takada, H; Ebisui, K

    1989-02-01

    A case of brain metastasis from transitional cell carcinoma of the bladder that attained complete remission by methotrexate-vinblastine-adriamycin-cisplatin (M-VAC) therapy was reported. The patient was a 53-year-old male, already treated with total cystectomy and CAP therapy against pulmonary metastasis, which disappeared completely. At 8 months after complete remission of pulmonary metastasis, brain metastasis was found. One course of M-VAC therapy brought a complete remission persisting for 7 months. He is alive with no relapse.

  18. EGFR-Mutated Breast Metastasis of Lung Adenocarcinoma: A Case Report

    PubMed Central

    Dansin, Eric; Carnot, Aurélien; Servent, Véronique; Daussay, Dorothée; Robin, Yves-Marie; Surmei-Pintilie, Ecaterina; Lauridant, Géraldine; Descarpentries, Clothilde; Révillion, Françoise; Delattre, Claire

    2015-01-01

    Breast metastasis from other primary carcinoma is very rare and could be difficult to identify despite immunohistochemistry analysis. Breast metastasis from lung adenocarcinoma can mimic triple-negative breast cancer. Given the prognosis and therapeutic challenges, a correct diagnosis appears essential, and molecular biomarkers could be useful. We report the case of a 52-year-old woman with a breast mass initially diagnosed as primary breast cancer and secondarily attached to breast metastasis from an EGFR-mutated lung adenocarcinoma. The same activating EGFR mutations were identified in both the primary lung carcinoma and the breast metastasis. PMID:25873885

  19. DLC1-dependent parathyroid hormone–like hormone inhibition suppresses breast cancer bone metastasis

    PubMed Central

    Wang, Yufeng; Lei, Rong; Zhuang, Xueqian; Zhang, Ning; Pan, Hong; Li, Gang; Hu, Jing; Pan, Xiaoqi; Tao, Qian; Fu, Da; Xiao, Jianru; Chin, Y. Eugene; Kang, Yibin; Yang, Qifeng; Hu, Guohong

    2014-01-01

    Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β–induced expression of parathyroid hormone–like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho–TGF-β crosstalk in osteolytic bone metastasis. PMID:24590291

  20. The Mechanics of Metastasis: Insights from a Computational Model

    PubMed Central

    Brodland, G. Wayne; Veldhuis, Jim H.

    2012-01-01

    Although it may seem obvious that mechanical forces are required to drive metastatic cell movements, understanding of the mechanical aspects of metastasis has lagged far behind genetic and biochemical knowledge. The goal of this study is to learn about the mechanics of metastasis using a cell-based finite element model that proved useful for advancing knowledge about the forces that drive embryonic cell and tissue movements. Metastasis, the predominant cause of cancer-related deaths, involves a series of mechanical events in which one or more cells dissociate from a primary tumour, migrate through normal tissue, traverse in and out of a multi-layer circulatory system vessel and resettle. The present work focuses on the dissemination steps, from dissociation to circulation. The model shows that certain surface tension relationships must be satisfied for cancerous cells to dissociate from a primary tumour and that these equations are analogous to those that govern dissociation of embryonic cells. For a dissociated cell to then migrate by invadopodium extension and contraction and exhibit the shapes seen in experiments, the invadopodium must generate a contraction equal to approximately twice that produced by the interfacial tension associated with surrounding cells. Intravasation through the wall of a vessel is governed by relationships akin to those in the previous two steps, while release from the vessel wall is governed by equations that involve surface and interfacial tensions. The model raises a number of potential research questions. It also identifies how specific mechanical properties and the sub-cellular structural components that give rise to them might be changed so as to thwart particular metastatic steps and thereby block the spread of cancer. PMID:23028513

  1. En Bloc Resection of Solitary Functional Secreting Spinal Metastasis.

    PubMed

    Goodwin, C Rory; Clarke, Michelle J; Gokaslan, Ziya L; Fisher, Charles; Laufer, Ilya; Weber, Michael H; Sciubba, Daniel M

    2016-05-01

    Study Design Literature review. Objective Functional secretory tumors metastatic to the spine can secrete hormones, growth factors, peptides, and/or molecules into the systemic circulation that cause distinct syndromes, clinically symptomatic effects, and/or additional morbidity and mortality. En bloc resection has a limited role in metastatic spine disease due to the current paradigm that systemic burden usually determines morbidity and mortality. Our objective is to review the literature for studies focused on en bloc resection of functionally active spinal metastasis as the primary indication. Methods A review of the PubMed literature was performed to identify studies focused on functional secreting metastatic tumors to the spinal column. We identified five cases of patients undergoing en bloc resection of spinal metastases from functional secreting tumors. Results The primary histologies of these spinal metastases were pheochromocytoma, carcinoid tumor, choriocarcinoma, and a fibroblast growth factor 23-secreting phosphaturic mesenchymal tumor. Although studies of en bloc resection for these rare tumor subtypes are confined to case reports, this surgical treatment option resulted in metabolic cures and decreased clinical symptoms postoperatively for patients diagnosed with solitary functional secretory spinal metastasis. Conclusion Although the ability to formulate comprehensive conclusions is limited, case reports demonstrate that en bloc resection may be considered as a potential surgical option for the treatment of patients diagnosed with solitary functional secretory spinal metastatic tumors. Future prospective investigations into clinical outcomes should be conducted comparing intralesional resection and en bloc resection for patients diagnosed with solitary functional secretory spinal metastasis.

  2. DNA Damage Response Genes and the Development of Cancer Metastasis

    PubMed Central

    Broustas, Constantinos G.; Lieberman, Howard B.

    2014-01-01

    DNA damage response genes play vital roles in the maintenance of a healthy genome. Defects in cell cycle checkpoint and DNA repair genes, especially mutation or aberrant downregulation, are associated with a wide spectrum of human disease, including a predisposition to the development of neurodegenerative conditions and cancer. On the other hand, upregulation of DNA damage response and repair genes can also cause cancer, as well as increase resistance of cancer cells to DNA damaging therapy. In recent years, it has become evident that many of the genes involved in DNA damage repair have additional roles in tumorigenesis, most prominently by acting as transcriptional (co-) factors. Although defects in these genes are causally connected to tumor initiation, their role in tumor progression is more controversial and it seems to depend on tumor type. In some tumors like melanoma, cell cycle checkpoint/DNA repair gene upregulation is associated with tumor metastasis, whereas in a number of other cancers the opposite has been observed. Several genes that participate in the DNA damage response, such as RAD9, PARP1, BRCA1, ATM and TP53 have been associated with metastasis by a number of in vitro biochemical and cellular assays, by examining human tumor specimens by immunohistochemistry or by DNA genomewide gene expression profiling. Many of these genes act as transcriptional effectors to regulate other genes implicated in the pathogenesis of cancer. Furthermore, they are aberrantly expressed in numerous human tumors and are causally related to tumorigenesis. However, whether the DNA damage repair function of these genes is required to promote metastasis or another activity is responsible (e.g., transcription control) has not been determined. Importantly, despite some compelling in vitro evidence, investigations are still needed to demonstrate the role of cell cycle checkpoint and DNA repair genes in regulating metastatic phenotypes in vivo. PMID:24397478

  3. CXCL12-γ in primary tumors drives breast cancer metastasis.

    PubMed

    Ray, P; Stacer, A C; Fenner, J; Cavnar, S P; Meguiar, K; Brown, M; Luker, K E; Luker, G D

    2015-04-16

    Compelling evidence shows that chemokine C-X-C motif chemokine ligand 12 (CXCL12) drives metastasis in multiple malignancies. Similar to other key cytokines in cancer, CXCL12 exists as several isoforms with distinct biophysical properties that may alter signaling and functional outputs. However, effects of CXCL12 isoforms in cancer remain unknown. CXCL12-α, -β and -γ showed cell-type-specific differences in activating signaling through G protein-dependent pathways in cell-based assays, while CXCL12-γ had greatest effects on recruitment of the adapter protein β-arrestin 2. CXCL12-β and -γ also stimulated endothelial tube formation to a greater extent than CXCL12-α. To investigate the effects of CXCL12 isoforms on tumor growth and metastasis, we used a mouse xenograft model of metastatic human breast cancer combining CXCR4+ breast cancer cells and mammary fibroblasts secreting an isoform of CXCL12. Altough all CXCL12 isoforms produced comparable growth of mammary tumors, CXCL12-γ significantly increased metastasis to bone marrow and other sites. Breast cancer cells originating from tumors with CXCL12-γ fibroblasts upregulated RANKL (receptor activator of nuclear factor-κB ligand), contributing to bone marrow tropism of metastatic cancer cells. CXCL12-γ was expressed in metastatic tissues in mice, and we also detected CXCL12-γ in malignant pleural effusions from patients with breast cancer. In our mouse model, mammary fibroblasts disseminated to sites of breast cancer metastases, providing another mechanism to increase levels of CXCL12 in metastatic environments. These studies identify CXCL12-γ as a potent pro-metastatic molecule with important implications for cancer biology and effective therapeutic targeting of CXCL12 pathways.

  4. Platelets contribute to growth and metastasis in hepatocellular carcinoma.

    PubMed

    Bihari, Chhagan; Rastogi, Archana; Shasthry, Saggere Muralikrishna; Bajpai, Meenu; Bhadoria, Ajeet Singh; Rajesh, S; Mukund, Amar; Kumar, Anupam; Sarin, Shiv K

    2016-09-01

    To determine the association of platelets with hepatocellular carcinoma (HCC) growth and its metastasis. We examined platelets, laboratory, and radiological data of consecutive 420 HCC and 1008 cirrhosis cases. Follow-up information of platelet count in cirrhosis to HCC, pre- to post-therapy, and post-therapy to HCC outcome was analyzed. Cytokine profiling was performed in HCC and cirrhosis (n = 10 each). On the basis of imaging, HCC was divided into six subgroups. Cytosmears of HCC were assessed for platelet clustering around tumor cells. An in vitro Matrigel invasion assay was performed on human HCC cell lines using graded concentration of platelets. Baseline platelet numbers and platelet/lymphocyte ratios (PLRs) were significantly higher (p < 0.001) in HCC than cirrhosis. IL-1, IL-6, FGF, G-CSF, thrombopoietin, and VEGF were higher in HCC than cirrhosis. Platelet counts were increased after HCC conversion of cirrhosis (p < 0.001) and decreased (p < 0.001) after therapy. Platelets and PLR in recurrence cases were higher than in responders at baseline. AFP, PIVKAII, platelets, and PLR increase (p < 0.001 each) with advancement in HCC growth. Multivariate analysis showed platelets (p = 0.002), PLR (p = 0.004), and AFP (p < 0.001) associated with distant metastasis. Platelet clustering seen in 75.7% of HCC group 3, 45% in group 2, and 12.5% in group 1 cases (p < 0.001). Invaded cells in Matrigel assay positively correlated with platelet concentration. Platelets can contribute to the development, growth, invasion, and metastasis of HCC. Rising platelet count after HCC therapy is indicative of incomplete response or recurrence. PMID:27457354

  5. CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis

    PubMed Central

    Ray, Paramita; Stacer, Amanda C.; Fenner, Joseph; Cavnar, Stephen P.; Meguiar, Kaille; Brown, Martha; Luker, Kathryn E.; Luker, Gary D.

    2014-01-01

    Compelling evidence shows that chemokine CXCL12 drives metastasis in multiple malignancies. Similar to other key cytokines in cancer, CXCL12 exists as several isoforms with distinct biophysical properties that may alter signaling and functional outputs. However, effects of CXCL12 isoforms in cancer remain unknown. CXCL12-α, β, and γ showed cell-type specific differences in activating signaling through G protein-dependent pathways in cell-based assays, while CXCL12-γ had greatest effects on recruitment of the adapter protein β-arrestin 2. CXCL12-β and γ also stimulated endothelial tube formation to a greater extent than CXCL12-α. To investigate effects of CXCL12 isoforms on tumor growth and metastasis, we used a mouse xenograft model of metastatic human breast cancer combining CXCR4+ breast cancer cells and mammary fibroblasts secreting an isoform of CXCL12. While all CXCL12 isoforms produced comparable growth of mammary tumors, CXCL12-γ significantly increased metastasis to bone marrow and other sites. Breast cancer cells originating from tumors with CXCL12-γ fibroblasts upregulated RANKL, contributing to bone marrow tropism of metastatic cancer cells. CXCL12-γ was expressed in metastatic tissues in mice, and we also detected CXCL12-γ in malignant pleural effusions from patients with breast cancer. In our mouse model, mammary fibroblasts disseminated to sites of breast cancer metastases, providing another mechanism to increase levels of CXCL12 in metastatic environments. These studies identify CXCL12-γ as a potent pro-metastatic molecule with important implications for cancer biology and effective therapeutic targeting of CXCL12 pathways. PMID:24909174

  6. Thyroid metastasis as initial presentation of clear cell renal carcinoma

    PubMed Central

    Ramírez-Plaza, César Pablo; Domínguez-López, Marta Elena; Blanco-Reina, Francisco

    2015-01-01

    Introduction Metastatic tumors account for 1.4–2.5% of thyroid malignancies. About 25–30% of patients with clear cell renal carcinoma (CCRC) have distant metastasis at the time of diagnosis, being the thyroid gland a rare localization [5%]. Presentation of the case A 62-year woman who underwent a cervical ultrasonography and a PAAF biopsy reporting atypical follicular proliferation with a few intranuclear vacuoles “suggestive” of thyroid papillary cancer in the context of a multinodular goiter was reported. A total thyroidectomy was performed and the histology of a clear cell renal carcinoma (CCRC) was described in four nodules of the thyroid gland. A CT scan was performed and a renal giant right tumor was found. The patient underwent an eventful radical right nephrectomy and the diagnosis of CCRC was confirmed. Discussion Thyroid metastasis (TM) from CCRC are usually apparent in a metachronic context during the follow-up of a treated primary (even many years after) but may sometimes be present at the same time than the primary renal tumor. Our case is exceptional because the TM was the first evidence of the CCRC, which was subsequently diagnosed and treated. Conclusion The possibility of finding of an incidental metastatic tumor in the thyroid gland from a previous unknown and non-diganosed primary (as CCRC in our case was) is rare and account only for less than 1% of malignancies. Nonetheless, the thyroid gland is a frequent site of metastasis and the presence of “de novo” thyroid nodules in oncologic patients must be always considered and studied. PMID:25827295

  7. En Bloc Resection of Solitary Functional Secreting Spinal Metastasis

    PubMed Central

    Goodwin, C. Rory; Clarke, Michelle J.; Gokaslan, Ziya L.; Fisher, Charles; Laufer, Ilya; Weber, Michael H.; Sciubba, Daniel M.

    2015-01-01

    Study Design Literature review. Objective Functional secretory tumors metastatic to the spine can secrete hormones, growth factors, peptides, and/or molecules into the systemic circulation that cause distinct syndromes, clinically symptomatic effects, and/or additional morbidity and mortality. En bloc resection has a limited role in metastatic spine disease due to the current paradigm that systemic burden usually determines morbidity and mortality. Our objective is to review the literature for studies focused on en bloc resection of functionally active spinal metastasis as the primary indication. Methods A review of the PubMed literature was performed to identify studies focused on functional secreting metastatic tumors to the spinal column. We identified five cases of patients undergoing en bloc resection of spinal metastases from functional secreting tumors. Results The primary histologies of these spinal metastases were pheochromocytoma, carcinoid tumor, choriocarcinoma, and a fibroblast growth factor 23–secreting phosphaturic mesenchymal tumor. Although studies of en bloc resection for these rare tumor subtypes are confined to case reports, this surgical treatment option resulted in metabolic cures and decreased clinical symptoms postoperatively for patients diagnosed with solitary functional secretory spinal metastasis. Conclusion Although the ability to formulate comprehensive conclusions is limited, case reports demonstrate that en bloc resection may be considered as a potential surgical option for the treatment of patients diagnosed with solitary functional secretory spinal metastatic tumors. Future prospective investigations into clinical outcomes should be conducted comparing intralesional resection and en bloc resection for patients diagnosed with solitary functional secretory spinal metastasis. PMID:27099819

  8. Delayed liver metastasis of a meningeal solitary fibrous tumor.

    PubMed

    Buccauw, Kurt; Sciot, Raf; Wolter, Pascal; Aerts, Raymond; Claus, Filip

    2011-12-01

    Solitary fibrous tumors (SFT's) are rare soft tissue neoplasms of mesenchymal origin, most commonly reported in the thoracic cavity. They exhibit an aggressive and infiltrative nature and have a tendency to recur either locally or distantly, the latter typically being a late event. Primary therapy consists of complete excision and prognosis is poor in case of recurrence. In this manuscript, we discuss the imaging features and treatment options for a patient presenting with delayed liver metastasis ten years after treatment for a meningeal SFT.

  9. Non-small cell lung carcinoma metastasis to the anus.

    PubMed

    Dhandapani, Ramya Gowri; Anosike, Chinedum; Ganguly, Akash

    2016-01-01

    A 70-year-old man presenting with a lung mass was investigated and treated with pneumonectomy for adenocarcinoma of the lung. He re-presented 3 months later with a large perianal abscess and mass. Subsequent investigations and biopsies showed disseminated metastases from the lung primary. Immunohistochemical staining confirmed the nature of the anal metastasis from the lung adenocarcinoma. Lung cancer is notorious for metastases, hence it is important to be aware of the uncommon modes of spread, which will help obtain early diagnosis and optimise treatment. PMID:27130556

  10. Role of the autonomic nervous system in tumorigenesis and metastasis

    PubMed Central

    Magnon, Claire

    2015-01-01

    Convergence of multiple stromal cell types is required to develop a tumorigenic niche that nurtures the initial development of cancer and its dissemination. Although the immune and vascular systems have been shown to have strong influences on cancer, a growing body of evidence points to a role of the nervous system in promoting cancer development. This review discusses past and current research that shows the intriguing role of autonomic nerves, aided by neurotrophic growth factors and axon cues, in creating a favorable environment for the promotion of tumor formation and metastasis. PMID:27308436

  11. Cancer as a Proinflammatory Environment: Metastasis and Cachexia

    PubMed Central

    Inácio Pinto, Nelson; Carnier, June; Oyama, Lila M.; Otoch, Jose Pinhata; Alcântara, Paulo Sergio; Tokeshi, Flavio; Nascimento, Claudia M.

    2015-01-01

    The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines. PMID:26508818

  12. Zebrafish-based systems pharmacology of cancer metastasis.

    PubMed

    Shimada, Yasuhito; Nishimura, Yuhei; Tanaka, Toshio

    2014-01-01

    Because of their small size, high fecundity, and commonality to human genetics and genomics, phenotype-based animal testing using zebrafish (Danio rerio) has emerged as a powerful tool for identifying disease mechanisms, drug target molecules and small bioactive compounds over the last decade. Importantly, the immaturity of the zebrafish larvae immune system compared with that of mammals facilitates the implantation of human tumors representing aggressive cancer progression with metastasis. In the current chapter, we describe the methods for human cancer cell xenotransplantation into zebrafish, phenotypic image analysis, and transcriptome analysis using deep sequencing.

  13. Paeoniflorin inhibits macrophage-mediated lung cancer metastasis.

    PubMed

    Wu, Qi; Chen, Gang-Ling; Li, Ya-Juan; Chen, Yang; Lin, Fang-Zhen

    2015-12-01

    Alternatively activated macrophages are more frequently involved in tumor growth, angiogenesis, and immunosuppression. A previous study showed that paeoniflorin, the major active constituent of Paeonia lactiflora Pallas, can inhibit tumor growth and lung metastases of Lewis lung tumor-bearing mice. This study tried to investigate whether paeoniflorin inhibited lung cancer metastasis by inhibiting the alternative activation of macrophages (M2 macrophage). Using a viability assay, the cytotoxicity of paeoniflorin on Lewis lung cancer cells and peritoneal macrophages were investigated. In vitro scratch wound and in vivo lung metastasis experiments were used to test the ability to inhibit the migration of paeoniflorin and the function of M2 macrophages. Flow cytometry was performed to test the cell cycle of Lewis lung cancer cells, and to test the M2 macrophages in peritoneal macrophages and subcutaneous transplantable tumor. It was found that paeoniflorin showed no inhibitory effect on the growth of Lewis lung cancer cells and peritoneal macrophages of mouse in vitro. Paeoniflorin could attenuate the migration of LLC stimulated by alternatively activated macrophages (stimulated for 24 h and 48 h, paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 or P < 0.05 vs control group). Paeoniflorin could decrease the cell populations at S phases (paeoniflorin 10, 30, 100 μmol·L(-1), P < 0.05 vs control group) and increase the cell populations at G0-G1 phases of Lewis lung cancer cells (paeoniflorin 100 μmol·L(-1), P < 0.05 vs control group) and reduce the numbers of M2 macrophages in peritoneal macrophages induced by IL-4 (paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 vs Control group). Paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft and decrease the numbers of M2 macrophages in subcutaneous xenograft tumour in vivo (paeoniflorin 20, 40 mg·kg(-1), P < 0.01 vs control group). These results suggest that paeoniflorin could reduce

  14. Epithelial-myoepithelial carcinoma metastasis to the thoracic spine.

    PubMed

    Goodwin, C Rory; Khattab, Mohamed H; Sankey, Eric W; Crane, Genevieve M; McCarthy, Edward F; Sciubba, Daniel M

    2016-02-01

    Epithelial-myoepithelial carcinoma (EMC) is a very rare salivary gland malignancy accounting for less than 1% of salivary gland tumors, and classically arises from the parotid gland in females. Spinal cord compression caused by EMC metastasized from the parotid gland has only been described once in the literature to our knowledge. We report the first case of a patient with parotid EMC spinal metastasis undergoing a gross total resection with instrumented fusion. This case illustrates that an en bloc resection with a planned transgression through the spinal canal may be a reasonable option for EMC metastasized to the spine. PMID:26474503

  15. Vertebral Metastasis as the Initial Manifestation of Colon Cancer

    PubMed Central

    Jain, Tushina; Williams, Renee; Liechty, Benjamin

    2016-01-01

    Oncology guidelines currently recommend against performing colonoscopies in the workup of adenocarcinoma of unknown primary unless colonic malignancy is otherwise suggested by clinical signs or symptoms. We present 2 cases of metastatic colonic adenocarcinoma that presented only with neurologic symptoms from vertebral metastasis. Although bony metastases are a rare presentation of colon cancer and colonoscopy is not warranted in the initial workup of adenocarcinoma of unknown primary, we describe these cases as a reminder that bony metastases do not rule out a colon cancer diagnosis. PMID:27807574

  16. Radiotherapy for a phalanx bone metastasis of a lung adenocarcinoma.

    PubMed

    Sumodhee, Shakeel; Huchot, Eric; Peret, Gaelle; Marchal, Christian; Paganin, Fabrice; Magnin, Valerie

    2014-09-01

    Phalanx bone metastasis as the initial presenting sign of lung cancer is a rare presentation. Lung cancer is known to metastasize to the bone, but rarely to the fingers. A 61-year-old male smoker presented with pain in the left ring finger. Severe pain discouraged the patient from using his left hand. An X-ray of the left hand showed a lytic bone lesion. The patient was treated with finger radiotherapy. Analgesics were no longer needed and the patient was able to reuse his left hand in his everyday life. Palliative radiotherapy relieved our patient and improved his quality of life. PMID:25493086

  17. Cancer as a Proinflammatory Environment: Metastasis and Cachexia.

    PubMed

    Inácio Pinto, Nelson; Carnier, June; Oyama, Lila M; Otoch, Jose Pinhata; Alcântara, Paulo Sergio; Tokeshi, Flavio; Nascimento, Claudia M

    2015-01-01

    The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines.

  18. Extracranial oral cavity metastasis from glioblastoma multiforme: A case report

    PubMed Central

    Kup, Philipp Günther; Nieder, Carsten; Winnekendonk, Guido; Adamietz, Irenäus Anton; Fakhrian, Khashayar

    2016-01-01

    Glioblastoma multiforme is the most common primary malignant brain tumor. The clinical outcome following diagnosis remains extremely poor. The treatment of choice is wide surgical resection of the visible tumor, frequently followed by adjuvant combined radiochemotherapy (RCTx) with temozolomide as the chemotherapeutic agent. Extracranial metastases are extremely rare, with <200 cases of extracranial metastases from glioblastoma multiforme reported in the literature to date. We herein present a case of a patient suffering from a fast-growing metastasis to the oral cavity, completely filling the buccal cavity within 2 weeks, as the only manifestation of recurrent glioblastoma multiforme following initial surgical resection and adjuvant RCTx.

  19. Paeoniflorin inhibits macrophage-mediated lung cancer metastasis.

    PubMed

    Wu, Qi; Chen, Gang-Ling; Li, Ya-Juan; Chen, Yang; Lin, Fang-Zhen

    2015-12-01

    Alternatively activated macrophages are more frequently involved in tumor growth, angiogenesis, and immunosuppression. A previous study showed that paeoniflorin, the major active constituent of Paeonia lactiflora Pallas, can inhibit tumor growth and lung metastases of Lewis lung tumor-bearing mice. This study tried to investigate whether paeoniflorin inhibited lung cancer metastasis by inhibiting the alternative activation of macrophages (M2 macrophage). Using a viability assay, the cytotoxicity of paeoniflorin on Lewis lung cancer cells and peritoneal macrophages were investigated. In vitro scratch wound and in vivo lung metastasis experiments were used to test the ability to inhibit the migration of paeoniflorin and the function of M2 macrophages. Flow cytometry was performed to test the cell cycle of Lewis lung cancer cells, and to test the M2 macrophages in peritoneal macrophages and subcutaneous transplantable tumor. It was found that paeoniflorin showed no inhibitory effect on the growth of Lewis lung cancer cells and peritoneal macrophages of mouse in vitro. Paeoniflorin could attenuate the migration of LLC stimulated by alternatively activated macrophages (stimulated for 24 h and 48 h, paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 or P < 0.05 vs control group). Paeoniflorin could decrease the cell populations at S phases (paeoniflorin 10, 30, 100 μmol·L(-1), P < 0.05 vs control group) and increase the cell populations at G0-G1 phases of Lewis lung cancer cells (paeoniflorin 100 μmol·L(-1), P < 0.05 vs control group) and reduce the numbers of M2 macrophages in peritoneal macrophages induced by IL-4 (paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 vs Control group). Paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft and decrease the numbers of M2 macrophages in subcutaneous xenograft tumour in vivo (paeoniflorin 20, 40 mg·kg(-1), P < 0.01 vs control group). These results suggest that paeoniflorin could reduce

  20. Breast Cancer Metastasis Suppressor 1 (BRMS1): Robust Biological and Pathological Data, But Still Enigmatic Mechanism of Action.

    PubMed

    Welch, D R; Manton, C A; Hurst, D R

    2016-01-01

    Metastasis requires coordinated expression of multiple genetic cassettes, often via epigenetic regulation of gene transcription. BRMS1 blocks metastasis, but not orthotopic tumor growth in multiple tumor types, presumably via SIN3 chromatin remodeling complexes. Although there is an abundance of strong data supporting BRMS1 as a metastasis suppressor, the mechanistic data directly connecting molecular pathways with inhibition of particular steps in metastasis are not well defined. In this review, the data for BRMS1-mediated metastasis suppression in multiple tumor types are discussed along with the steps in metastasis that are inhibited. PMID:27613131

  1. Active Tobacco Smoking and Distant Metastasis in Patients With Oropharyngeal Cancer

    SciTech Connect

    McBride, Sean M.; Ali, Nawal N.; Margalit, Danielle N.; Chan, Annie W.

    2012-09-01

    Purpose: Distant metastasis is the site of first relapse in approximately one-third of patients with locally advanced oropharyngeal carcinoma, irrespective of human papillomavirus status. Yet the risk factors associated with distant metastasis are not well characterized. We sought to characterize the relationship between smoking status and distant metastasis. Methods and Materials: We evaluated the association between tobacco smoking status and distant metastasis in a retrospective cohort study of 132 patients who underwent definitive radiation therapy and chemotherapy for Stage III-IVA/B oropharyngeal cancer. Information on tobacco smoking was prospectively collected by patient questionnaires and physician notes at the time of diagnosis. Thirty-three percent of the patients were nonsmokers, 51% were former smokers, 16% were active smokers. The cumulative lifetime tobacco smoking in pack-years was 20 (range, 0-150). Results: With a median follow-up time of 52 months, the overall rate of distant metastasis at 4 years was 8%. Distant metastasis was the most common first site of relapse, occurring in 56% of the patients with recurrences. Active smokers had higher rates of distant metastasis than non-active smokers (including never- and former smokers; 31% vs. 4%, p < 0.001) and former smokers (31% vs. 3%, p < 0.001). There was no statistically significant difference in the risk of distant metastasis for patients with lifetime cumulative pack-years >20 and {<=}20 (10% vs. 4%, p = 0.19). In univariate analysis, active smoking (p = 0.0004) and N category (p = 0.009) were predictive of increased risk of distant metastasis. In multivariate analysis, active smoking was the most significant predictive factor for increased risk of distant metastasis (hazard ratio, 12.7, p < 0.0001). Conclusions: This study identified a strong association between active smoking and distant metastasis in patients with oropharyngeal cancer.

  2. The molecular effect of metastasis suppressors on Src signaling and tumorigenesis: new therapeutic targets

    PubMed Central

    Liu, Wensheng; Kovacevic, Zaklina; Peng, Zhihai; Jin, Runsen; Wang, Puxiongzhi; Yue, Fei; Zheng, Minhua; Huang, Michael L-H.; Jansson, Patric J.; Richardson, Vera; Kalinowski, Danuta S.; Lane, Darius J.R.; Merlot, Angelica M.; Sahni, Sumit; Richardson, Des R.

    2015-01-01

    A major problem for cancer patients is the metastasis of cancer cells from the primary tumor. This involves: (1) migration through the basement membrane; (2) dissemination via the circulatory system; and (3) invasion into a secondary site. Metastasis suppressors, by definition, inhibit metastasis at any step of the metastatic cascade. Notably, Src is a non-receptor, cytoplasmic, tyrosine kinase, which becomes aberrantly activated in many cancer-types following stimulation of plasma membrane receptors (e.g., receptor tyrosine kinases and integrins). There is evidence of a prominent role of Src in tumor progression-related events such as the epithelial–mesenchymal transition (EMT) and the development of metastasis. However, the precise molecular interactions of Src with metastasis suppressors remain unclear. Herein, we review known metastasis suppressors and summarize recent advances in understanding the mechanisms of how these proteins inhibit metastasis through modulation of Src. Particular emphasis is bestowed on the potent metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1) and its interactions with the Src signaling cascade. Recent studies demonstrated a novel mechanism through which NDRG1 plays a significant role in regulating cancer cell migration by inhibiting Src activity. Moreover, we discuss the rationale for targeting metastasis suppressor genes as a sound therapeutic modality, and we review several examples from the literature where such strategies show promise. Collectively, this review summarizes the essential interactions of metastasis suppressors with Src and their effects on progression of cancer metastasis. Moreover, interesting unresolved issues regarding these proteins as well as their potential as therapeutic targets are also discussed. PMID:26431493

  3. How do bisphosphonates inhibit bone metastasis in vivo?

    PubMed

    Fournier, Pierrick G; Stresing, Verena; Ebetino, Frank H; Clézardin, Philippe

    2010-07-01

    Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and have demonstrated clinical utility in the treatment of patients with osteolytic bone metastases. They also exhibit direct antitumor activity in vitro and can reduce skeletal tumor burden and inhibit the formation of bone metastases in vivo. However, whether such effects are caused by a direct action of bisphosphonates on tumor cells or indirectly through inhibition of bone resorption remains unclear. To address this question, we used here a structural analog of the bisphosphonate risedronate, NE-58051, which has a bone mineral affinity similar to that of risedronate, but a 3000-fold lower bone antiresorptive activity. In vitro, risedronate and NE-58051 inhibited proliferation of breast cancer and melanoma cell lines. In vivo, risedronate and NE-58051 did not inhibit the growth of subcutaneous B02 breast tumor xenografts or the formation of B16F10 melanoma lung metastasis. In contrast to NE-58051, risedronate did inhibit B02 breast cancer bone metastasis formation by reducing both bone destruction and skeletal tumor burden, indicating that the antitumor effect of bisphosphonates is achieved mainly through inhibition of osteoclast-mediated bone resorption.

  4. Monitoring tumor metastasis by in vivo imaging and flow cytometer

    NASA Astrophysics Data System (ADS)

    Gu, Zhenqin; Guo, Jin; Liu, Guangda; Li, Yan; Chen, Yun; Chen, Tong; Wang, Chen; Wei, Xunbin

    2009-08-01

    Prostate cancer is the most common malignancy in American men and the second leading cause of deaths from cancer, after lung cancer. The tumor usually grows slowly and remains confined to the gland for many years. During this time, the tumor produces little or no symptoms or outward signs. As the cancer advances, however, it can metastasize throughout other areas of the body, such as the bones, lungs, and liver. Surgical resection, hormonal therapy, chemotherapy and radiation therapy are the foundation of current prostate cancer therapies. Treatments for prostate cause both short- and long-term side effects that may be difficult to accept. Molecular mechanisms of prostate cancer metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of cancer cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern prostate cancer cell spread through the microenvironment in vivo in real-time confocal nearinfrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess prostate cancer cell spreading and the circulation kinetics of prostate cancer cells. A real- time quantitative monitoring of circulating prostate cancer cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

  5. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis

    PubMed Central

    Wu, Jason Boyang; Shao, Chen; Li, Xiangyan; Li, Qinlong; Hu, Peizhen; Shi, Changhong; Li, Yang; Chen, Yi-Ting; Yin, Fei; Liao, Chun-Peng; Stiles, Bangyan L.; Zhau, Haiyen E.; Shih, Jean C.; Chung, Leland W.K.

    2014-01-01

    Tumors from patients with high-grade aggressive prostate cancer (PCa) exhibit increased expression of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines. Despite the association between MAOA and aggressive PCa, it is unclear how MAOA promotes PCa progression. Here, we found that MAOA functions to induce epithelial-to-mesenchymal transition (EMT) and stabilize the transcription factor HIF1α, which mediates hypoxia through an elevation of ROS, thus enhancing growth, invasiveness, and metastasis of PCa cells. Knockdown and overexpression of MAOA in human PCa cell lines indicated that MAOA induces EMT through activation of VEGF and its coreceptor neuropilin-1. MAOA-dependent activation of neuropilin-1 promoted AKT/FOXO1/TWIST1 signaling, allowing FOXO1 binding at the TWIST1 promoter. Importantly, the MAOA-dependent HIF1α/VEGF-A/FOXO1/TWIST1 pathway was activated in high-grade PCa specimens, and knockdown of MAOA reduced or even eliminated prostate tumor growth and metastasis in PCa xenograft mouse models. Pharmacological inhibition of MAOA activity also reduced PCa xenograft growth in mice. Moreover, high MAOA expression in PCa tissues correlated with worse clinical outcomes in PCa patients. These findings collectively characterize the contribution of MAOA in PCa pathogenesis and suggest that MAOA has potential as a therapeutic target in PCa. PMID:24865426

  6. Nanotechnology-based intelligent drug design for cancer metastasis treatment.

    PubMed

    Gao, Yu; Xie, Jingjing; Chen, Haijun; Gu, Songen; Zhao, Rongli; Shao, Jingwei; Jia, Lee

    2014-01-01

    Traditional chemotherapy used today at clinics is mainly inherited from the thinking and designs made four decades ago when the Cancer War was declared. The potency of those chemotherapy drugs on in-vitro cancer cells is clearly demonstrated at even nanomolar levels. However, due to their non-specific effects in the body on normal tissues, these drugs cause toxicity, deteriorate patient's life quality, weaken the host immunosurveillance system, and result in an irreversible damage to human's own recovery power. Owing to their unique physical and biological properties, nanotechnology-based chemotherapies seem to have an ability to specifically and safely reach tumor foci with enhanced efficacy and low toxicity. Herein, we comprehensively examine the current nanotechnology-based pharmaceutical platforms and strategies for intelligent design of new nanomedicines based on targeted drug delivery system (TDDS) for cancer metastasis treatment, analyze the pros and cons of nanomedicines versus traditional chemotherapy, and evaluate the importance that nanomaterials can bring in to significantly improve cancer metastasis treatment.

  7. Vertebral hemangioma coincident with metastasis of colon adenocarcinoma.

    PubMed

    Zapałowicz, Krzysztof; Bierzyńska-Macyszyn, Grażyna; Stasiów, Bartłomiej; Krzan, Aleksandra; Wierzycka, Beata; Kopycka, Anna

    2016-03-01

    The authors report on colon cancer metastasis to the L-3 vertebra, which had been previously found to be involved by an asymptomatic hemangioma. A 61-year-old female patient was admitted after onset of lumbar axial pain and weakness of the right quadriceps muscle. Her medical history included colon cancer that had been diagnosed 3 years earlier and was treated via a right hemicolectomy followed by chemotherapy. Presurgical imaging revealed an asymptomatic hemangioma in the L-3 vertebral body. Computed tomography and MRI of the spine were performed after admission and revealed a hemangioma in the L-3 vertebral body as well as a soft-tissue mass protruding from the L-3 vertebral body to the spinal canal. Treatment consisted of vertebroplasty of the hemangioma, left L-3 hemilaminectomy, and removal of the pathological mass from the spinal canal and the L-3 vertebral body. Histopathological examination revealed the presence of colon cancer metastasis and a hemangioma in the same vertebra.

  8. AIF inhibits tumor metastasis by protecting PTEN from oxidation.

    PubMed

    Shen, Shao-Ming; Guo, Meng; Xiong, Zhong; Yu, Yun; Zhao, Xu-Yun; Zhang, Fei-Fei; Chen, Guo-Qiang

    2015-11-01

    Apoptosis-inducing factor (AIF) exerts dual roles on cell death and survival, but its substrates as a putative oxidoreductase and roles in tumorigenesis remain elusive. Here, we report that AIF physically interacts with and inhibits the oxidation of phosphatase and tensin homolog on chromosome ten (PTEN), a tumor suppressor susceptible for oxidation-mediated inactivation. More intriguingly, we also identify PTEN as a mitochondrial protein and the ectopic expression of mitochondrial targeting sequence-carrying PTEN almost completely inhibits Akt phosphorylation in PTEN-deficient cells. AIF knockdown causes oxidation-mediated inactivation of the lipid phosphatase activity of PTEN, with ensuing activation of Akt kinase, phosphorylation of the Akt substrate GSK-3β, and activation of β-catenin signaling in cancer cells. Through its effect on β-catenin signaling, AIF inhibits epithelial-mesenchymal transition (EMT) and metastasis of cancer cells in vitro and in orthotopically implanted xenografts. Accordingly, the expression of AIF is correlated with the survival of human patients with cancers of multiple origins. These results identify PTEN as the substrate of AIF oxidoreductase and reveal a novel function for AIF in controlling tumor metastasis.

  9. Mouse Models of Brain Metastasis for Unravelling Tumour Progression.

    PubMed

    Soto, Manuel Sarmiento; Sibson, Nicola R

    2016-01-01

    Secondary tumours in the brain account for 40 % of triple negative breast cancer patients, and the percentage may be higher at the time of autopsy. The use of in vivo models allow us to recapitulate the molecular mechanisms potentially used by circulating breast tumour cells to proliferate within the brain.Metastasis is a multistep process that depends on the success of several stages including cell evasion from the primary tumour, distribution and survival within the blood stream and cerebral microvasculature, penetration of the blood-brain barrier and proliferation within the brain microenvironment. Cellular adhesion molecules are key proteins involved in all of the steps in the metastatic process. Our group has developed two different in vivo models to encompass both seeding and colonisation stages of the metastatic process: (1) haematogenous dissemination of tumour cells by direct injection into the left ventricle of the heart, and (2) direct implantation of the tumour cells into the mouse brain.This chapter describes, in detail, the practical implementation of the intracerebral model, which can be used to analyse tumour proliferation within a specific area of the central nervous system and tumour-host cell interactions. We also describe the use of immunohistochemistry techniques to identify, at the molecular scale, tumour-host cell interactions, which may open new windows for brain metastasis therapy.

  10. An Orthotopic Murine Model of Human Prostate Cancer Metastasis

    PubMed Central

    Pavese, Janet; Ogden, Irene M.; Bergan, Raymond C.

    2013-01-01

    Our laboratory has developed a novel orthotopic implantation model of human prostate cancer (PCa). As PCa death is not due to the primary tumor, but rather the formation of distinct metastasis, the ability to effectively model this progression pre-clinically is of high value. In this model, cells are directly implanted into the ventral lobe of the prostate in Balb/c athymic mice, and allowed to progress for 4-6 weeks. At experiment termination, several distinct endpoints can be measured, such as size and molecular characterization of the primary tumor, the presence and quantification of circulating tumor cells in the blood and bone marrow, and formation of metastasis to the lung. In addition to a variety of endpoints, this model provides a picture of a cells ability to invade and escape the primary organ, enter and survive in the circulatory system, and implant and grow in a secondary site. This model has been used effectively to measure metastatic response to both changes in protein expression as well as to response to small molecule therapeutics, in a short turnaround time. PMID:24084571

  11. Vertebral Compression Fracture Related to Pancreatic Cancer With Osteoblastic Metastasis

    PubMed Central

    Chih, Yu-Pin; Wu, Wei-Ting; Lin, Chien-Lin; Jou, Herng-Jeng; Huang, Yu-Hsuan; Chen, Liang-Chi; Chou, Li-Wei

    2016-01-01

    Abstract Compression fracture of the vertebral body is common in the older patients. The possible etiology like osteoporosis or cancer metastasis should be included as a possibility in the differential diagnosis for severe back pain, to prevent delays in diagnosis and treatment. More severe fractures can cause significant pain, leading to inability to perform activities of daily living, and life-threatening in the older patient. We report a rare case of a 61-year-old man suffering from severe lower back pain and intermittent abdominal fullness. He came to our clinic, where muscle power was normal, but could not stand up or change posture because of severe back pain. Plain film and magnetic resonance imaging of lumbar spine both revealed osteoblastic lesion at L2 spine. Abdomen computed tomography showed a mass at the pancreatic body. The pancreatic cancer with osteoblastic metastasis was diagnosed. After receiving multimodality therapy such as percutaneous vertebroplasty and pain controlling, we provided effective palliation of symptoms, aggressive rehabilitation program, and better quality of life. Our case highlights the benefits of multidisciplinary cancer treatment for such patient, preventing the complications such as immobilization accompanied with adverse effects like musculoskeletal, respiratory, and cardiovascular systems. All clinicians should be informed of the clinical findings to provide patients with suitable therapies and surveys. PMID:26844499

  12. [Ileus caused by metastasis of cutaneous malignant melanoma: case report].

    PubMed

    Fajdić, Josip; Durović, Drazen; Gotovac, Nikola; Gugić, Damir; Stastny, Tomislav; Slisurić, Ferdinand

    2011-01-01

    In this case report we describe rare metastatic appearance of cutaneous malignant melanoma ( MM) in small intestine followed by clinical appearance of acute surgical abdomen. A 42-year old women operated in our hospital in April 2009. due to unusual naevus on her right arm. Pathologicaly it was MM grossly 1.5 cm, microscopically Breslow 11 mm, Clark's level IV (T4), number of mitosis 1.4 per mm2, without ulcerations. She was sent to continue treatment at the National Referal Center for Melanoma in KB "S. milosrdnice" Zagreb, Croatia. A month later wider excision (3 cm free margin) and sentinel lymph node biopsy (SLNB) was made there followed by axillary lymphadenectomy due to positive axillary finding. She received six cycles of chemotherapy. She arrived in our hospital in May 2010, under clinical picture of small intestine ileus and acute surgical abdomen. After preparation she was operated the same day. The cause of ileus was metastasis of MM in the small interstine. We made intestinal resection with termino-terminal anastomosis. The patient was released to home care ten days after operation without any complication. This case report demonstrates rarely described case of MM metastasis in the small intestine found causing ileus. PMID:22359897

  13. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis

    PubMed Central

    Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Pavlides, Stephanos; Whitaker-Menezes, Diana; Pestell, Richard G; Howell, Anthony

    2011-01-01

    In 1889, Dr. Stephen Paget proposed the “seed and soil” hypothesis, which states that cancer cells (the seeds) need the proper microenvironment (the soil) for them to grow, spread and metastasize systemically. In this hypothesis, Dr. Paget rightfully recognized that the tumor microenvironment has an important role to play in cancer progression and metastasis. In this regard, a series of recent studies have elegantly shown that the production of hydrogen peroxide, by both cancer cells and cancer-associated fibroblasts, may provide the necessary “fertilizer,” by driving accelerated aging, DNA damage, inflammation and cancer metabolism, in the tumor microenvironment. By secreting hydrogen peroxide, cancer cells and fibroblasts are mimicking the behavior of immune cells (macrophages/neutrophils), driving local and systemic inflammation, via the innate immune response (NFκB). Thus, we should consider using various therapeutic strategies (such as catalase and/or other antioxidants) to neutralize the production of cancer-associated hydrogen peroxide, thereby preventing tumor-stroma co-evolution and metastasis. The implications of these findings for overcoming chemo-resistance in cancer cells are also discussed in the context of hydrogen peroxide production and cancer metabolism. PMID:21734470

  14. Sur8 mediates tumorigenesis and metastasis in colorectal cancer

    PubMed Central

    Lee, Young-Mi; Kaduwal, Saluja; Lee, Kug Hwa; Park, Jong-Chan; Jeong, Woo-Jeong; Choi, Kang-Yell

    2016-01-01

    Sur8, a scaffold protein of the Ras pathway, interacts with Ras and Raf and modulates the Ras-extracellular signal-regulated kinase (ERK) pathway. Here we show that Sur8 is overexpressed in established human colorectal cancer (CRC) cell lines and CRC patient tissues. Moreover, Sur8 expression is increased during liver metastasis in CRC patients. Sur8 knockdown decreases ERK and Akt activities in CRC cell lines, regardless of their K-Ras, B-Raf or PI3K mutation status. Overexpression or knockdown of Sur8 increases or decreases, respectively, the proliferation or transformation of CRC cell lines. Sur8 knockdown attenuates the migration and invasion of HCT116 CRC cells. Subcutaneous or orthotopic injection of HCT116 cells harboring a doxycycline (Dox)-mediated Sur8 knockdown system in nude mice resulted in decreased tumorigenic potential and inhibited the liver metastatic potential of HCT116 cells. Taken together, our data support the role of Sur8 as a promoter of tumorigenesis and liver metastasis in CRC through its modulation of the Ras-ERK and PI3K-Akt signaling pathways. PMID:27469030

  15. Sur8 mediates tumorigenesis and metastasis in colorectal cancer.

    PubMed

    Lee, Young-Mi; Kaduwal, Saluja; Lee, Kug Hwa; Park, Jong-Chan; Jeong, Woo-Jeong; Choi, Kang-Yell

    2016-01-01

    Sur8, a scaffold protein of the Ras pathway, interacts with Ras and Raf and modulates the Ras-extracellular signal-regulated kinase (ERK) pathway. Here we show that Sur8 is overexpressed in established human colorectal cancer (CRC) cell lines and CRC patient tissues. Moreover, Sur8 expression is increased during liver metastasis in CRC patients. Sur8 knockdown decreases ERK and Akt activities in CRC cell lines, regardless of their K-Ras, B-Raf or PI3K mutation status. Overexpression or knockdown of Sur8 increases or decreases, respectively, the proliferation or transformation of CRC cell lines. Sur8 knockdown attenuates the migration and invasion of HCT116 CRC cells. Subcutaneous or orthotopic injection of HCT116 cells harboring a doxycycline (Dox)-mediated Sur8 knockdown system in nude mice resulted in decreased tumorigenic potential and inhibited the liver metastatic potential of HCT116 cells. Taken together, our data support the role of Sur8 as a promoter of tumorigenesis and liver metastasis in CRC through its modulation of the Ras-ERK and PI3K-Akt signaling pathways. PMID:27469030

  16. Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer.

    PubMed

    Wu, Buchu; Hu, Ke; Li, Shu; Zhu, Jing; Gu, Liying; Shen, Haoran; Hambly, Brett D; Bao, Shisan; Di, Wen

    2012-01-01

    Dihydroartiminisin (DHA), the active component of a Chinese herb (Artemisia annua), has been utilised as an anti-malarial drug since ancient China. DHA has also been shown to inhibit proliferation of cancer in vitro. However, the capacity of DHA to inhibit the development of ovarian cancer is still unclear. The adhesion, invasion, and migration of human ovarian cancer cell line (HO8910PM) was determined following DHA treatment in vitro, using Matrigel coated plate, transwell membrane chamber, and wound healing models, respectively. A mouse ovarian cancer model was established by orthotopic inoculation of HO8910PM cell line in nude mice. The growth and metastasis in vivo was determined 8 weeks post-implantation in response to DHA treatment. The expression of phosphorylated focal adhesion kinase (pFAK) and matrix metalloproteinases (MMP-2 and MMP-9) was evaluated using Western blotting. The expression of Von Willebrand factor (vWF) and infiltration of macrophages were determined, using immunohistochemistry. DHA inhibits ovarian cancer cell proliferation, adhesion, migration and invasion in vitro in a dose-dependent manner, consistent with decreased expression of pFAK and MMP-2, but not MMP-9. DHA inhibited metastasis significantly in vivo, associated with reduced vWF expression and macrophage infiltration. In conclusion, DHA inhibits the development of ovarian cancer, in part via down-regulating pFAK, MMP-2, vWF and macrophage infiltration. PMID:22025319

  17. Thrombocytosis of Liver Metastasis from Colorectal Cancer as Predictive Factor.

    PubMed

    Jósa, Valéria; Krzystanek, Marcin; Vass, Tamás; Lang, Tamás; Juhász, Viktória; Szilágyi, Kamilla; Tihanyi, Balázs; Harsányi, László; Szállási, Zoltán; Salamon, Ferenc; Baranyai, Zsolt

    2015-09-01

    There is increasing evidence that thrombocytosis is associated with tumor invasion and metastasis formation. It was shown in several solid tumor types that thrombocytosis prognosticates cancer progression. The aim of this study was to evaluate preoperative thrombocytosis as a potential prognostic biomarker in isolated metastases, in patients with liver metastasis of colorectal cancer (mCRC). Clinicopathological data of 166 patients with mCRC who had surgical resection between 2001 and 2011 were collected retrospectively. All primary tumors have been already resected. The platelet count was evaluated based on the standard preoperative blood profile. The patients were followed-up on average for 28 months. Overall survival (OS) of patients with thrombocytosis was significantly worse both in univariate (HR = 3.00, p = 0.03) and in multivariate analysis (HR = 4.68, p = 0.056) when adjusted for gender, age, tumor size and surgical margin. Thrombocytosis was also a good prognosticator of disease-free survival (DFS) with HR = 2.7, p = 0.018 and nearly significant in multivariate setting (HR = 2.26, p = 0.073). The platelet count is a valuable prognostic marker for the survival in patients with mCRC.

  18. Role of EMT in Metastasis and Therapy Resistance

    PubMed Central

    Smith, Bethany N.; Bhowmick, Neil A.

    2016-01-01

    Epithelial–mesenchymal transition (EMT) is a complex molecular program that regulates changes in cell morphology and function during embryogenesis and tissue development. EMT also contributes to tumor progression and metastasis. Cells undergoing EMT expand out of and degrade the surrounding microenvironment to subsequently migrate from the primary site. The mesenchymal phenotype observed in fibroblasts is specifically important based on the expression of smooth muscle actin (α-SMA), fibroblast growth factor (FGF), fibroblast-specific protein-1 (FSP1), and collagen to enhance EMT. Although EMT is not completely dependent on EMT regulators such as Snail, Twist, and Zeb-1/-2, analysis of upstream signaling (i.e., TGF-β, EGF, Wnt) is necessary to understand tumor EMT more comprehensively. Tumor epithelial–fibroblast interactions that regulate tumor progression have been identified during prostate cancer. The cellular crosstalk is significant because these events influence therapy response and patient outcome. This review addresses how canonical EMT signals originating from prostate cancer fibroblasts contribute to tumor metastasis and recurrence after therapy. PMID:26828526

  19. Immune escape mechanisms in colorectal cancer pathogenesis and liver metastasis.

    PubMed

    Pancione, Massimo; Giordano, Guido; Remo, Andrea; Febbraro, Antonio; Sabatino, Lina; Manfrin, Erminia; Ceccarelli, Michele; Colantuoni, Vittorio

    2014-01-01

    Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced or de novo synthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance.

  20. Vascular targeting of a gold nanoparticle to breast cancer metastasis

    PubMed Central

    Peiris, Pubudu M.; Deb, Partha; Doolittle, Elizabeth; Doron, Gilad; Goldberg, Amy; Govender, Priya; Shah, Shruti; Rao, Swetha; Carbone, Sarah; Cotey, Thomas; Sylvestre, Meilyn; Singh, Sohaj; Schiemann, William P.; Lee, Zhenghong; Karathanasis, Efstathios

    2015-01-01

    The vast majority of breast cancer deaths are due to metastatic disease. While deep tissue targeting of nanoparticles is suitable for some primary tumors, vascular targeting may be a more attractive strategy for micrometastasis. This study combined a vascular targeting strategy with the enhanced targeting capabilities of a nanoparticle to evaluate the ability of a gold nanoparticle to specifically target the early spread of metastatic disease. As a ligand for the vascular targeting strategy, we utilized a peptide targeting alpha(v) beta(3) integrin, which is functionally linked to the development of micrometastases at a distal site. By employing a straightforward radiolabeling method to incorporate Technetium-99m into the gold nanoparticles, we used the high sensitivity of radionuclide imaging to monitor the longitudinal accumulation of the nanoparticles in metastatic sites. Animal and histological studies showed that vascular targeting of the nanoparticle facilitated highly accurate targeting of micrometastasis in the 4T1 mouse model of breast cancer metastasis using radionuclide imaging and a low dose of the nanoparticle. Due to the efficient targeting scheme, 14% of the injected AuNP deposited at metastatic sites in the lungs within 60 min after injection, indicating that the vascular bed of metastasis is a viable target site for nanoparticles. PMID:26036431

  1. Transcriptional network analysis identifies BACH1 as a master regulator of breast cancer bone metastasis.

    PubMed

    Liang, Yajun; Wu, Heng; Lei, Rong; Chong, Robert A; Wei, Yong; Lu, Xin; Tagkopoulos, Ilias; Kung, Sun-Yuan; Yang, Qifeng; Hu, Guohong; Kang, Yibin

    2012-09-28

    The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes.

  2. Potential of targeted drug delivery system for the treatment of bone metastasis.

    PubMed

    Vinay, Raichur; KusumDevi, V

    2016-01-01

    Bone metastasis is a devastating complication of cancer that requires an immediate attention. Although our understanding of the metastatic process has improved over the years, yet a number of questions still remain unanswered, and more research is required for complete understanding of the skeletal consequences of metastasis. Furthermore, as no effective treatments are available for some of the most common skeleton disorders such as arthritis, osteoarthritis, osteosarcoma and metastatic bone cancer, there is an urgent need to develop new drugs and drug delivery systems for safe and efficient clinical treatments. Hence this article describes the potential of targeted delivery platforms aimed specifically at bone metastasized tumors. The review gives a brief understanding of the proposed mechanisms of metastasis and focuses primarily on the targeting moieties such as bisphosphonates, which represent the current gold standard in bone metastasis therapies. Special focus has been given to the targeted nanoparticulate systems for treating bone metastasis and its future. Also highlighted are some of the therapeutic targets that can be exploited for designing therapies for bone metastasis. Some of the patented molecules for bone metastasis prevention and treatment have also been discussed. Recently proposed HIFU-CHEM, which utilizes High Intensity Focused ultrasound (HIFU) guided by MRI in combination with temperature-sensitive nanomedicines has also been briefed. The study has been concluded with a focus on the innovations requiring an immediate attention that could improve the treatment modality of bone metastasis.

  3. Differences in Metabolic Programming Define the Site of Breast Cancer Cell Metastasis.

    PubMed

    Döppler, Heike; Storz, Peter

    2015-10-01

    Although metabolic reprogramming is a hallmark of oncogenic transformation and growth of primary tumor cells, little is known about how metabolic alterations impact metastasis. In this issue of Cell Metabolism, Dupuy et al. (2015) show that primary breast cancer cells display metabolic heterogeneity, and that their distinct metabolic programs define their sites of metastasis.

  4. High Risk of Lateral Nodal Metastasis in Lateral Solitary Solid Papillary Thyroid Cancer.

    PubMed

    Lai, Xing-Jian; Zhang, Bo; Jiang, Yu-Xin; Li, Jian-Chu; Zhao, Rui-Na; Yang, Xiao; Zhang, Qing; Zhang, Xiao-Yan; Li, Wen-Bo; Zhu, Shen-Ling

    2016-01-01

    We explored the relationship between ultrasonic intra-thyroidal location and neck node metastasis pattern in solitary solid papillary thyroid cancer (PTC). Data on 186 patients were retrospectively reviewed. The association between several characteristics and neck node metastasis pattern were analyzed. Among the 186 thyroid nodules, age ≥45 y (p = 0.005), mass size ≥2 cm (p = 0.001), presence of calcifications (p < 0.001) and lateral nodal metastasis (p = 0.001) were significantly related to central nodal metastasis in multivariate analysis. Mass size ≥2 cm (p = 0.046) and central nodal metastasis (p = 0.002) were significantly related to lateral nodal metastasis in multivariate analysis. Location of an intra-thyroidal solitary solid PTC located non-adjacent to the trachea (lateral) was significantly related to lateral nodal metastasis (p = 0.043) compared with location of an intra-thyroidal solitary solid PTC adjacent to the trachea (medial or isthmus). Lateral lesions have a high risk of lateral nodal metastasis in solitary solid PTC.

  5. Aggressive surgical resection for concomitant liver and lung metastasis in colorectal cancer

    PubMed Central

    Lee, Sung Hwan; Kim, Sung Hyun; Lim, Jin Hong; Kim, Sung Hoon; Lee, Jin Gu; Kim, Dae Joon; Choi, Gi Hong; Choi, Jin Sub

    2016-01-01

    Backgrounds/Aims Aggressive surgical resection for hepatic metastasis is validated, however, concomitant liver and lung metastasis in colorectal cancer patients is equivocal. Methods Clinicopathologic data from January 2008 through December 2012 were retrospectively reviewed in 234 patients with colorectal cancer with concomitant liver and lung metastasis. Clinicopathologic factors and survival data were analyzed. Results Of the 234 patients, 129 (55.1%) had synchronous concomitant liver and lung metastasis from colorectal cancer and 36 (15.4%) had metachronous metastasis. Surgical resection was performed in 33 patients (25.6%) with synchronous and 6 (16.7%) with metachronous metastasis. Surgical resection showed better overall survival in both groups (synchronous, p=0.001; metachronous, p=0.028). In the synchronous metastatic group, complete resection of both liver and lung metastatic lesions had better survival outcomes than incomplete resection of two metastatic lesions (p=0.037). The primary site of colorectal cancer and complete resection were significant prognostic factors (p=0.06 and p=0.003, respectively). Conclusions Surgical resection for hepatic and pulmonary metastasis in colorectal cancer can improve complete remission and survival rate in resectable cases. Colorectal cancer with concomitant liver and lung metastasis is not a poor prognostic factor or a contraindication for surgical treatments, hence, an aggressive surgical approach may be recommended in well-selected resectable cases. PMID:27621747

  6. Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the "Warburg Effect." Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerob...

  7. Overexpression of neuromedin U is correlated with regional metastasis of head and neck squamous cell carcinoma

    PubMed Central

    Wang, Lei; Chen, Chen; Li, Fen; Hua, Qing-Quan; Chen, Shiming; Xiao, Bokui; Dai, Mengyuan; Li, Man; Zheng, Anyuan; Yu, Di; Hu, Zhang Wei; Tao, Zezhang

    2016-01-01

    Regional metastasis is an important prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). Neuromedin U (Nmu) is a secreted neuropeptide, named due to its potent uterine contraction-inducing activity. The aim of the present study was to analyze the significance of Nmu in the regional metastasis of HNSCC. The characteristics of 240 patients recruited from the Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University (Wuhan, China) were summarized retrospectively. The positive rate of neck dissection was analyzed according to the material. The expression levels of Nmu in human tumor samples were analyzed using immunohistochemistry. Subsequently, the expression of Nmu was investigated using a tissue microassay to analyze the association between Nmu protein expression and Tumor Node Metastasis (TNM) status. The positive rate of neck dissection was 51.4% in the study sample. The expression levels of Nmu in primary tumors with regional metastasis were higher, compared with those without metastasis. There was increased protein expression of Nmu in the advanced tumor tissues. The data obtained in the present study demonstrated that the expression of Nmu was correlated with regional metastasis and TNM status. Overexpression of Nmu may be involved in the process of regional metastasis of HNSCC, and may serve as a novel and valuable biomarker for predicting regional metastasis in patients with HNSCC. PMID:27279246

  8. Non-motorized voluntary running does not affect experimental and spontaneous metastasis in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study investigated the effects of non-motorized voluntary running on experimental metastasis of B16BL/6 melanoma and spontaneous metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice. After 9 weeks of running, mice (n = 30 per group) received an intravenous injection of B16BL/6 c...

  9. KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Identifying molecular targets for treatment of pancreatic cancer metastasis is critical due to the high frequency of dissemination prior to diagnosis of this lethal disease. Because the KISS1 metastasis suppressor is expressed at reduced levels in advanced pancreatic cancer, we hypothesized that re-...

  10. Individualized optimal surgical extent of the lateral neck in papillary thyroid cancer with lateral cervical metastasis.

    PubMed

    Park, Jae-Yong; Koo, Bon Seok

    2014-06-01

    Despite an excellent prognosis, cervical lymph node (LN) metastases are common in patients with papillary thyroid cancer (PTC). The presence of metastasis is associated with an increased risk of locoregional recurrence, which significantly impairs quality of life and may decrease survival. Therefore, it has been an important determinant of the extent of lateral LN dissection in the initial treatment of PTC patients with lateral cervical metastasis. However, the optimal extent of therapeutic lateral neck dissection (ND) remains controversial. Optimizing the surgical extent of LN dissection is fundamental for balancing the surgical morbidity and oncological benefits of ND in PTC patients with lateral neck metastasis. We reviewed the currently available literature regarding the optimal extent of lateral LN dissection in PTC patients with lateral neck metastasis. Even in cases with suspicion of metastatic LN at the single lateral level or isolated metastatic lateral LN, the application of ND including all sublevels from IIa and IIb to Va and Vb may be overtreatment, due to the surgical morbidity. When there is no suspicion of LN metastasis at levels II and V, or when multilevel aggressive neck metastasis is not found, sublevel IIb and Va dissection may not be necessary in PTC patients with lateral neck metastasis. Thus consideration of the individualized optimal surgical extent of lateral ND is important when treating PTC patients with lateral cervical metastasis.

  11. Metastasis signatures: genes regulating tumor-microenvironment interactions predict metastatic behavior.

    PubMed

    Albini, Adriana; Mirisola, Valentina; Pfeffer, Ulrich

    2008-03-01

    The possibility of predicting clinical outcome of cancer patients through the analysis of gene expression profiles in the primary tumor is a kind of ideological revolution as the multistep carcinogenesis model postulates that the proportion of cells within the primary tumor that actually acquire metastasis driving mutation(s) is small; too small to leave its imprint on the gene expression profile. The data collected to date have brought a new paradigm to reality in the metastasis field: metastasis must at least in part rely on mutations and/or gene regulation events present in the majority of cells which constitute the primary tumor mass. By analyses of differential expression of primary tumors versus metastases or by functional analyses of putative metastasis genes in experimental metastasis, many metastasis-associated gene expression events have been identified that correlate with the development of metastases. Among genes "favoring" metastasis, we find many molecules that are expressed not by the tumor cell itself but by the cells of the microenvironment, as well as genes over-expressed in the primary tumor that have a principle role in mediating tumor-host interactions. Here we review these concepts and advance hypotheses on how gene expression of the primary tumor and the microenvironment can favor the spread of the metastasis seeds and how this knowledge can provide tools to secondary prevention.

  12. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S.

    PubMed

    Sevenich, Lisa; Bowman, Robert L; Mason, Steven D; Quail, Daniela F; Rapaport, Franck; Elie, Benelita T; Brogi, Edi; Brastianos, Priscilla K; Hahn, William C; Holsinger, Leslie J; Massagué, Joan; Leslie, Christina S; Joyce, Johanna A

    2014-09-01

    Metastasis remains the most common cause of death in most cancers, with limited therapies for combating disseminated disease. While the primary tumour microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analysed tumour-stroma interactions that modulate organ tropism of brain, bone and lung metastasis in xenograft models. We identified a number of potential modulators of site-specific metastasis, including cathepsin S as a regulator of breast-to-brain metastasis. High cathepsin S expression at the primary site correlated with decreased brain metastasis-free survival in breast cancer patients. Both macrophages and tumour cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in vivo. Cathepsin S specifically mediates blood-brain barrier transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B. Pharmacological inhibition of cathepsin S significantly reduced experimental brain metastasis, supporting its consideration as a therapeutic target for this disease.

  13. Down-Regulation of WAVE3, a Metastasis Promoter Gene, Inhibits Invasion and Metastasis of Breast Cancer Cells

    PubMed Central

    Sossey-Alaoui, Khalid; Safina, Alfiya; Li, Xiurong; Vaughan, Mary M.; Hicks, David G.; Bakin, Andrei V.; Cowell, John K.

    2007-01-01

    The expression of WAVE3, an actin-cytoskeleton and reorganization protein, is elevated in malignant human breast cancer, yet the role of WAVE3 in promoting tumor progression remains undefined. We have recently shown that knockdown of WAVE3 expression in human breast adenocarcinoma MDA-MB-231 cells using small interfering RNA resulted in a significant reduction of cell motility, migration, and invasion, which correlated with a reduction in the levels of active p38 mitogen-activated protein kinase. Here, we investigated the effect of stable suppression of WAVE3 by short hairpin RNA on tumor growth and metastasis in xenograft models. Breast cancer MDA-MB-231 cells expressing short hairpin RNA to WAVE3 (shWAVE3) showed a significant reduction in Matrigel invasion and formation of lung colonies after tail-vein injection in SCID mice. In the orthotopic model, we observed a reduction in growth rate of the primary tumors, as well as in the metastases to the lungs. We also show that suppression of p38 mitogen-activated protein kinase activity by dominant-negative p38 results in comparable phenotypes to the knockdown of WAVE3. These studies provide direct evidence that the WAVE3-p38 pathway contributes to breast cancer progression and metastasis. PMID:17525277

  14. TEL2 suppresses metastasis by down-regulating SERPINE1 in nasopharyngeal carcinoma.

    PubMed

    Sang, Yi; Chen, Ming-Yuan; Luo, Donghua; Zhang, Ru-Hua; Wang, Li; Li, Mei; Luo, Rongzhen; Qian, Chao-Nan; Shao, Jian-Yong; Zeng, Yi-Xin; Kang, Tiebang

    2015-10-01

    Metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC). However, the molecular mechanisms of NPC metastasis are poorly understood. Here, using our customized gene microarray containing all of the known human transcription factors and the current markers for epithelial-mesenchymal transition, we report that TEL2 was down-regulated in highly metastatic NPC cells and the metastatic tissues in lymph node. Mechanistically, TEL2 inhibits the cell migration and invasion in vitro and metastasis in vivo by directly suppressing the SERPINE1 promoter in NPC. Consistently, an inverse correlation was observed between the protein levels of TEL2 and SERPINE1 using clinical NPC samples. Collectively, we have provided the first evidence that TEL2 plays a key role in NPC metastasis by directly down-regulating SERPINE1, and that this novel axis of TEL2 / SERPINE1 may be valuable to develop new strategies for treating NPC patients with metastasis.

  15. Biomaterials for Abrogating Metastasis: Bridging the Gap between Basic and Translational Research.

    PubMed

    Conde, João; Shomron, Noam; Artzi, Natalie

    2016-09-01

    Herein lies the issue of how to best approach cancer metastasis therapeutics in a focused, directed and efficacious manner. The lack of standardized means to efficiently deliver therapeutic cargo to metastatic sites calls for a paradigm shift in the way we view and treat metastasis. It is crucial to leverage the potential of nanomedicine to differentially combat cancer spread at each stage of the disease (primary tumor growth and formation of metastases) while considering the optimal administration route. We propose to implement three possible strategies to treat cancer as a function of disease type and state, while leveraging the advancement in materials design and in particular nanotechnology: (1) local primary tumor abrogation; (2) primary tumor re-programming to prevent metastasis; and (3) combination (local and systemic) therapy when metastasis has already transpired. Herein, we highlight potential means to bridge the gap between basic and translational research as related to metastasis therapy. PMID:27457877

  16. TEL2 suppresses metastasis by down-regulating SERPINE1 in nasopharyngeal carcinoma.

    PubMed

    Sang, Yi; Chen, Ming-Yuan; Luo, Donghua; Zhang, Ru-Hua; Wang, Li; Li, Mei; Luo, Rongzhen; Qian, Chao-Nan; Shao, Jian-Yong; Zeng, Yi-Xin; Kang, Tiebang

    2015-10-01

    Metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC). However, the molecular mechanisms of NPC metastasis are poorly understood. Here, using our customized gene microarray containing all of the known human transcription factors and the current markers for epithelial-mesenchymal transition, we report that TEL2 was down-regulated in highly metastatic NPC cells and the metastatic tissues in lymph node. Mechanistically, TEL2 inhibits the cell migration and invasion in vitro and metastasis in vivo by directly suppressing the SERPINE1 promoter in NPC. Consistently, an inverse correlation was observed between the protein levels of TEL2 and SERPINE1 using clinical NPC samples. Collectively, we have provided the first evidence that TEL2 plays a key role in NPC metastasis by directly down-regulating SERPINE1, and that this novel axis of TEL2 / SERPINE1 may be valuable to develop new strategies for treating NPC patients with metastasis. PMID:26335051

  17. An Osteopontin/CD44 Axis in RhoGDI2-Mediated Metastasis Suppression.

    PubMed

    Ahmed, Mansoor; Sottnik, Joseph L; Dancik, Garrett M; Sahu, Divya; Hansel, Donna E; Theodorescu, Dan; Schwartz, Martin A

    2016-09-12

    RhoGDI2 specifically suppresses bladder cancer metastasis but not primary tumor growth, which involves tumor-associated macrophages. We report that macrophage-secreted osteopontin binds to CD44s on the tumor cells and promotes invasion and clonal growth. These effects are RhoGDI2-sensitive and require CD44s binding to the Rac GEF TIAM1. Osteopontin expression correlates with tumor aggressiveness and poor clinical outcome in patients. Inhibiting this pathway potently blocked lung and lymph node metastasis; however, primary tumors and established metastasis were less sensitive. Osteopontin-CD44s-TIAM1 promotes clonal growth in vitro but not at high cell density. These data identify osteopontin-CD44-TIAM1-Rac1 axis as a RhoGDI2-sensitive pathway and potential therapeutic target in bladder cancer metastasis. They also elucidate the mechanism behind RhoGDI2 specificity for metastasis over established tumors. PMID:27593345

  18. Biomechanical forces in the skeleton and their relevance to bone metastasis: biology and engineering considerations

    PubMed Central

    Lynch, Maureen; Fischbach, Claudia

    2014-01-01

    Bone metastasis represents the leading cause of breast cancer related-deaths. However, the effect of skeleton-associated biomechanical signals on the initiation, progression, and therapy response of breast cancer bone metastasis is largely unknown. This review seeks to highlight possible functional connections between skeletal mechanical signals and breast cancer bone metastasis and their contribution to clinical outcome. It provides an introduction to the physical and biological signals underlying bone functional adaptation and discusses the modulatory roles of mechanical loading and breast cancer metastasis in this process. Following a definition of biophysical design criteria, in vitro and in vivo approaches from the fields of bone biomechanics and tissue engineering will be reviewed that may be suitable to investigate breast cancer bone metastasis as a function of varied mechano-signaling. Finally, an outlook of future opportunities and challenges associated with this newly emerging field will be provided. PMID:25174311

  19. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism

    PubMed Central

    Yang, Yunlong; Zhang, Yin; Iwamoto, Hideki; Hosaka, Kayoko; Seki, Takahiro; Andersson, Patrik; Lim, Sharon; Fischer, Carina; Nakamura, Masaki; Abe, Mitsuhiko; Cao, Renhai; Skov, Peter Vilhelm; Chen, Fang; Chen, Xiaoyun; Lu, Yongtian; Nie, Guohui; Cao, Yihai

    2016-01-01

    The impact of discontinuation of anti-VEGF cancer therapy in promoting cancer metastasis is unknown. Here we show discontinuation of anti-VEGF treatment creates a time-window of profound structural changes of liver sinusoidal vasculatures, exhibiting hyper-permeability and enlarged open-pore sizes of the fenestrated endothelium and loss of VE-cadherin. The drug cessation caused highly leaky hepatic vasculatures permit tumour cell intravasation and extravasation. Discontinuation of an anti-VEGF antibody-based drug and sunitinib markedly promotes liver metastasis. Mechanistically, host hepatocyte, but not tumour cell-derived vascular endothelial growth factor (VEGF), is responsible for cancer metastasis. Deletion of hepatocyte VEGF markedly ablates the ‘off-drug'-induced metastasis. These findings provide mechanistic insights on anti-VEGF cessation-induced metastasis and raise a new challenge for uninterrupted and sustained antiangiogenic therapy for treatment of human cancers. PMID:27580750

  20. Gastric metastasis of renal cell carcinoma 20 years after radical nephrectomy

    PubMed Central

    Akay, Ebru; Kala, Mehtap; Karaman, Hatice

    2016-01-01

    Renal cell carcinomas account for 2–3% of malignant neoplasms in adults. The lung, soft tissues and bone represent the most frequent sites of distant metastasis in renal cell carcinoma. Gastric metastasis is rare. Our case was a 72-year-old man with complaints of fatigue and loss of appetite. In history, he had unergone radical nephrectomy due to renal cell carcinoma in 1993. A polypoid lesion was observed in upper gastrointestinal endoscopy. Histopathology of gastric biopsy specimen was reported as renal cell carcinoma. In English literature, there are 50 cases diagnosed as gastric metastasis from renal cell carcinoma. To date, there are only 4 cases with extremely late gastric metastasis of renal cell carcinoma. Herein, we present a rare case which underwent radical nephrectomy due to renal cell carcinoma and found to have gastric metastasis at 20. year of his follow-up. PMID:27274897

  1. Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol

    SciTech Connect

    Maeda, Masayo; Murakami, Manabu; Takegami, Tsutomu; Ota, Takahide

    2008-06-01

    Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonly used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent.

  2. Four-protein signature accurately predicts lymph node metastasis and survival in oral squamous cell carcinoma.

    PubMed

    Zanaruddin, Sharifah Nurain Syed; Saleh, Amyza; Yang, Yi-Hsin; Hamid, Sharifah; Mustafa, Wan Mahadzir Wan; Khairul Bariah, A A N; Zain, Rosnah Binti; Lau, Shin Hin; Cheong, Sok Ching

    2013-03-01

    The presence of lymph node (LN) metastasis significantly affects the survival of patients with oral squamous cell carcinoma (OSCC). Successful detection and removal of positive LNs are crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the LNs, where up to a third of clinically diagnosed metastasis-negative (N0) patients actually have metastasis-positive LNs in the neck. We developed a molecular signature in the primary tumor that could predict LN metastasis in OSCC. A total of 211 cores from 55 individuals were included in the study. Eleven proteins were evaluated using immunohistochemical analysis in a tissue microarray. Of the 11 biomarkers evaluated using receiver operating curve analysis, epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2/neu), laminin, gamma 2 (LAMC2), and ras homolog family member C (RHOC) were found to be significantly associated with the presence of LN metastasis. Unsupervised hierarchical clustering-demonstrated expression patterns of these 4 proteins could be used to differentiate specimens that have positive LN metastasis from those that are negative for LN metastasis. Collectively, EGFR, HER-2/neu, LAMC2, and RHOC have a specificity of 87.5% and a sensitivity of 70%, with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated that the LN signature could independently predict disease-specific survival (P = .036). The 4-protein LN signature validated in an independent set of samples strongly suggests that it could reliably distinguish patients with LN metastasis from those who were metastasis-free and therefore could be a prognostic tool for the management of patients with OSCC.

  3. Four-protein signature accurately predicts lymph node metastasis and survival in oral squamous cell carcinoma.

    PubMed

    Zanaruddin, Sharifah Nurain Syed; Saleh, Amyza; Yang, Yi-Hsin; Hamid, Sharifah; Mustafa, Wan Mahadzir Wan; Khairul Bariah, A A N; Zain, Rosnah Binti; Lau, Shin Hin; Cheong, Sok Ching

    2013-03-01

    The presence of lymph node (LN) metastasis significantly affects the survival of patients with oral squamous cell carcinoma (OSCC). Successful detection and removal of positive LNs are crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the LNs, where up to a third of clinically diagnosed metastasis-negative (N0) patients actually have metastasis-positive LNs in the neck. We developed a molecular signature in the primary tumor that could predict LN metastasis in OSCC. A total of 211 cores from 55 individuals were included in the study. Eleven proteins were evaluated using immunohistochemical analysis in a tissue microarray. Of the 11 biomarkers evaluated using receiver operating curve analysis, epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2/neu), laminin, gamma 2 (LAMC2), and ras homolog family member C (RHOC) were found to be significantly associated with the presence of LN metastasis. Unsupervised hierarchical clustering-demonstrated expression patterns of these 4 proteins could be used to differentiate specimens that have positive LN metastasis from those that are negative for LN metastasis. Collectively, EGFR, HER-2/neu, LAMC2, and RHOC have a specificity of 87.5% and a sensitivity of 70%, with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated that the LN signature could independently predict disease-specific survival (P = .036). The 4-protein LN signature validated in an independent set of samples strongly suggests that it could reliably distinguish patients with LN metastasis from those who were metastasis-free and therefore could be a prognostic tool for the management of patients with OSCC. PMID:23026198

  4. Outcomes in patients with brain metastasis from esophageal carcinoma

    PubMed Central

    Kothari, Nishi; Mellon, Eric; Hoffe, Sarah E.; Frakes, Jessica; Shridhar, Ravi; Pimiento, Jose; Meredith, Ken; Tran, Nam D.; Saeed, Nadia

    2016-01-01

    Background Brain metastases from esophageal carcinoma have historically been rare and associated with poor prognosis. With improvements in systemic disease control, the incidence of brain metastases is expected to rise. To better inform management decisions, we sought to identify factors associated with survival in patients with brain metastasis from esophageal cancer. Methods We retrospectively identified 49 patients with brain metastasis from stage I–IV primary esophageal cancer treated with surgery, radiation, or a combination of modalities at our tertiary referral center between 1998 and 2015. Medical records were reviewed to collect demographic and clinical information. Results Median age at diagnosis of the primary esophageal cancer was 60 years. Forty-one (84%) patients were male and forty patients (82%) had adenocarcinoma. Median overall survival (MS) following esophageal cancer diagnosis was 24 months (range, 3–71 months), and median survival after the identification of brain metastases was 5 months (range, 1–52 months). On univariate analysis, only patients with poor Karnofsky performance status (KPS <70), recursive partitioning analysis (RPA) classification (III), or 3 or more brain metastases were found to have worsened survival after the diagnosis of brain metastases (all P<0.01). Factors not associated with survival were age, gender, histology (adenocarcinoma vs. other), palliative-intent treatment of the primary tumor, time to diagnosis of brain metastases from initial diagnosis, uncontrolled primary tumor at time of brain metastasis diagnosis, or extracranial metastases. On multivariate analysis (MVA, KPS excluded), patients with RPA class I (MS, 14.6 months) or II (MS, 5.0 months) disease had significantly improved overall survival compared to class III disease (MS, 1.6 months, P<0.01). Also on MVA, patients with 1 (MS, 10.7 months) or 2 (MS, 4.7 months) brain metastases had significantly improved overall survival compared to patients with 3

  5. Evolution of cellular morpho-phenotypes in cancer metastasis

    PubMed Central

    Wu, Pei-Hsun; Phillip, Jude M.; Khatau, Shyam B.; Chen, Wei-Chiang; Stirman, Jeffrey; Rosseel, Sophie; Tschudi, Katherine; Van Patten, Joshua; Wong, Michael; Gupta, Sonal; Baras, Alexander S.; Leek, Jeffrey T.; Maitra, Anirban; Wirtz, Denis

    2015-01-01

    Intratumoral heterogeneity greatly complicates the study of molecular mechanisms driving cancer progression and our ability to predict patient outcomes. Here we have developed an automated high-throughput cell-imaging platform (htCIP) that allows us to extract high-content information about individual cells, including cell morphology, molecular content and local cell density at single-cell resolution. We further develop a comprehensive visually-aided morpho-phenotyping recognition (VAMPIRE) tool to analyze irregular cellular and nuclear shapes in both 2D and 3D microenvironments. VAMPIRE analysis of ~39,000 cells from 13 previously sequenced patient-derived pancreatic cancer samples indicate that metastasized cells present significantly lower heterogeneity than primary tumor cells. We found the same morphological signature for metastasis for a cohort of 10 breast cancer cell lines. We further decipher the relative contributions to heterogeneity from cell cycle, cell-cell contact, cell stochasticity and heritable morphological variations. PMID:26675084

  6. Unique Case Report of Pineal Gland Metastasis From Bladder Carcinoma.

    PubMed

    Li, Jun; Wang, Ping; Wang, Bin

    2016-05-01

    Pineal metastasis is uncommon and most metastatic pineal lesions are asymptomatic. To our knowledge the herein reported case is the first in which the pineal gland was confirmed as the metastatic site of a bladder carcinoma.The patient reported in this case is a 59-year-old man who suffered from headache and delirium for 4 days after surgical treatment for removal of a bladder carcinoma 1 year ago. Magnetic resonance imaging (MRI) revealed a solid tumor involving the pineal gland with significant enhancement.The patient underwent surgical treatment for removal of the neoplastic lesion in the pineal gland. Histopathological examination confirmed invasion of the pineal gland by metastatic urothelial carcinoma.This case highlighted that the presence of pineal lesions in patient with known malignancy should raise suspicion of metastatic involvement.

  7. Unique Case Report of Pineal Gland Metastasis From Bladder Carcinoma

    PubMed Central

    Li, Jun; Wang, Ping; Wang, Bin

    2016-01-01

    Abstract Pineal metastasis is uncommon and most metastatic pineal lesions are asymptomatic. To our knowledge the herein reported case is the first in which the pineal gland was confirmed as the metastatic site of a bladder carcinoma. The patient reported in this case is a 59-year-old man who suffered from headache and delirium for 4 days after surgical treatment for removal of a bladder carcinoma 1 year ago. Magnetic resonance imaging (MRI) revealed a solid tumor involving the pineal gland with significant enhancement. The patient underwent surgical treatment for removal of the neoplastic lesion in the pineal gland. Histopathological examination confirmed invasion of the pineal gland by metastatic urothelial carcinoma. This case highlighted that the presence of pineal lesions in patient with known malignancy should raise suspicion of metastatic involvement. PMID:27149501

  8. Psoralen inhibits bone metastasis of breast cancer in mice.

    PubMed

    Wu, Chunyu; Sun, Zhenping; Ye, Yiyi; Han, Xianghui; Song, Xiaoyun; Liu, Sheng

    2013-12-01

    Breast cancer is the most common female malignancy and it frequently metastasizes to bone. Metastatic breast cancer continues to be the primary cause of death for women in East and Southeast Asia. Psoralen is a furocoumarin that can be isolated from the seeds of Psoralea corylifolia L. Psoralen exhibits a wide range of biological properties and has been demonstrated as an antioxidant, antidepressant, anticancer, antibacterial, and antiviral agent. Additionally, it is involved in the formation and regulation of bone. This study investigated whether psoralen can inhibit metastasis of breast cancer to bone in vivo. Histological, molecular biological, and imaging analyses revealed that psoralen inhibits bone metastases in mice. Psoralen may function to inhibit breast cancer cell growth in the bone microenvironment and regulate the function of osteoblasts and osteoclasts in tumor-bearing mice. The results of this study suggest that psoralen is a bone-modifying agent and a potential therapeutic to treat patients with bone metastases.

  9. Brain metastasis detection by resonant Raman optical biopsy method

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Liu, Cheng-hui; Cheng, Gangge; Zhou, Lixin; Zhang, Chunyuan; Pu, Yang; Li, Zhongwu; Liu, Yulong; Li, Qingbo; Wang, Wei; Alfano, Robert R.

    2014-03-01

    Resonant Raman (RR) spectroscopy provides an effective way to enhance Raman signal from particular bonds associated with key molecules due to changes on a molecular level. In this study, RR is used for detection of human brain metastases of five kinds of primary organs of lung, breast, kidney, rectal and orbital in ex-vivo. The RR spectra of brain metastases cancerous tissues were measured and compared with those of normal brain tissues and the corresponding primary cancer tissues. The differences of five types of brain metastases tissues in key bio-components of carotene, tryptophan, lactate, alanine and methyl/methylene group were investigated. The SVM-KNN classifier was used to categorize a set of RR spectra data of brain metastasis of lung cancerous tissues from normal brain tissue, yielding diagnostic sensitivity and specificity at 100% and 75%, respectively. The RR spectroscopy may provide new moleculebased optical probe tools for diagnosis and classification of brain metastatic of cancers.

  10. Radiosensitive orbital metastasis as presentation of occult colonic adenocarcinoma

    PubMed Central

    Ludmir, Ethan B; McCall, Shannon J; Czito, Brian G; Palta, Manisha

    2014-01-01

    An 82-year-old man presented with progressive right frontal headaches. The patient's history was significant for benign polyps on surveillance colonoscopy 2 years prior, without high-grade dysplasia or carcinoma. MRI revealed an enhancing lesion arising within the superomedial aspect of the right orbit. Lesion biopsy demonstrated histological appearance and immunophenotype suggestive of colonic adenocarcinoma. Staging positron emission tomography/CT showed visceral metastases and diffuse activity in the posterior rectosigmoid, consistent with metastatic colon cancer. Treatment of the orbital lesion with external beam radiotherapy to 30 Gy resulted in significant palliation of the patient's headaches. The patient expired 2 months following treatment completion due to disease progression. Orbital metastasis as the initial presentation of an occult colorectal primary lesion is exceedingly rare, and occurred in this patient despite surveillance colonoscopy. Radiotherapy remains an efficacious modality for treatment of orbital metastases. PMID:25240005

  11. Intrameningioma Metastasis: Clinical Manifestation of Occult Primary Lung Carcinoma.

    PubMed

    Nadeem, Muhammad; Assad, Salman; Nasir, Humaira; Mansoor, Salman; Khan, Innayatullah; Manzoor, Hana; Kiani, Immad; Raja, Avais; Sulehria, Touqeer

    2016-01-01

    We report a case of lung carcinoma metastasizing into a meningioma in a 68-year-old female, who presented with progressively worsening right-sided hemiparesis and multiple episodes of adult onset epilepsy. Magnetic resonance imaging revealed an oval-shaped extra-axial hypointense lesion with a central hyperintense nodule in the left frontal region favoring a most probable diagnosis of a meningioma. Left frontoparietal craniotomy and excision of the tumor were carried out and histopathology with hematoxylin and eosin stain revealed a meningioma with metastatic adenocarcinoma and was confirmed by immunohistochemistry. The origin of metastasis was presumed to be from the lungs. A computed tomography (CT) scan of the chest with contrast showed a 3.1 x 2.9 cm mass with spiculated margins in the left lower lobe. Fine needle aspiration cytology (FNAC) proved it to be adenocarcinoma. PMID:27588225

  12. Intrameningioma Metastasis: Clinical Manifestation of Occult Primary Lung Carcinoma

    PubMed Central

    Nadeem, Muhammad; Nasir, Humaira; Mansoor, Salman; Khan, Innayatullah; Manzoor, Hana; Kiani, Immad; Raja, Avais; Sulehria, Touqeer

    2016-01-01

    We report a case of lung carcinoma metastasizing into a meningioma in a 68-year-old female, who presented with progressively worsening right-sided hemiparesis and multiple episodes of adult onset epilepsy. Magnetic resonance imaging revealed an oval-shaped extra-axial hypointense lesion with a central hyperintense nodule in the left frontal region favoring a most probable diagnosis of a meningioma. Left frontoparietal craniotomy and excision of the tumor were carried out and histopathology with hematoxylin and eosin stain revealed a meningioma with metastatic adenocarcinoma and was confirmed by immunohistochemistry. The origin of metastasis was presumed to be from the lungs. A computed tomography (CT) scan of the chest with contrast showed a 3.1 x 2.9 cm mass with spiculated margins in the left lower lobe. Fine needle aspiration cytology (FNAC) proved it to be adenocarcinoma. PMID:27588225

  13. Pancreatic metastasis from mycosis fungoides mimicking primary pancreatic tumor.

    PubMed

    Ceriolo, Paola; Fausti, Valentina; Cinotti, Elisa; Bonadio, Silvia; Raffaghello, Lizzia; Bianchi, Giovanna; Orcioni, Giulio Fraternali; Fiocca, Roberto; Rongioletti, Franco; Pistoia, Vito; Borgonovo, Giacomo

    2016-03-28

    Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that can undergo local progression with possible systemic dissemination. We report a case of a patient affected by MF with a pancreatic mass that was a diagnostic challenge between primitive tumor and pancreatic metastasis from MF. Clinical setting findings and imaging studies raised the suspicion of a pancreatic primary neoplasm. A diagnostic clue was provided by the combined histomorphologic/immunohistochemical study of pancreatic and cutaneous biopsies, which revealed a pancreatic localization of MF. Considering the rarity of metastatic localization of MF to the pancreas, we next investigated whether chemokine-chemokine receptor interactions could be involved in the phenomenon to provide new insight into the possible mechanisms underlying metastatic localization of MF to the pancreas. Histological analyses of archival pancreatic tissue demonstrated that glucagon-secreting cells of the pancreatic islets expressed the CCL27 chemokine, which may have attracted in our case metastatic MF cells expressing the complementary receptor CCR10.

  14. Aspergilloma Mimicking Metastasis in a Case with Laryngeal Carcinoma

    PubMed Central

    Demirtaş, Hakan; Çelik, Ahmet Orhan; Kayan, Mustafa; Umul, Ayşe; Döngel, İsa

    2016-01-01

    Introduction: Aspergilloma is a fungal ball which is composed of hyphal structure fungus, fibrin, mucus and cellular debris and settled in a pre-existing pulmonary cavity or an ectatic bronchial. It may cause colonization in patients with an immunosuppressive and underlying lung disease. Although chest radiography provides valuable information, it can be scanned more effectively by computed tomography (CT). Monitoring fungal ball within the cavity in CT provides establishing the diagnosis. Case report: However, in this case report, we presented a case with operated laryngeal carcinoma whom we first had considered to have metastasis and who had received a diagnosis of aspergilloma in CT and Positron emission tomography (PET). Conclusion: Imaging findings may remain limited in definitive diagnosis of aspergilloma. Therefore, surgical resection will allow for both pathological diagnosis and treatment. PMID:26980939

  15. Genes and pathways downstream of telomerase in melanoma metastasis

    PubMed Central

    Bagheri, Sepideh; Nosrati, Mehdi; Li, Shang; Fong, Sylvia; Torabian, Sima; Rangel, Javier; Moore, Dan H.; Federman, Scot; LaPosa, Rebecca R.; Baehner, Frederick L.; Sagebiel, Richard W.; Cleaver, James E.; Haqq, Christopher; Debs, Robert J.; Blackburn, Elizabeth H.; Kashani-Sabet, Mohammed

    2006-01-01

    Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects. First, reducing telomerase activity induced a more dendritic morphology, accompanied by increased melanin content and increased expression of tyrosinase, a key enzyme in melanin biosynthesis. Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production. Thus, telomerase activity controls the glycolytic pathway, potentially altering the energy state of tumor cells and thereby modulating tyrosinase activity and melanin production. These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis. PMID:16847266

  16. Non-functioning Aortocaval Paraganglioma Masquerading as Celiac Lymphnodal Metastasis.

    PubMed

    Gulavani, Nikhil; Rodrigues, Gabriel; Prabhu, Raghunath; Kamath, Ganesh; Rai, Lavanya; Rao, Lakshmi

    2014-02-01

    An extra-adrenal paraganglioma is a rare tumour derived from chromaffin cells of sympathetic ganglia. This report documents a rare case of a non-functional aortocaval paraganglioma in a 24-year-old woman with persistent abdominal pain. Computed tomography revealed a solid mass, measuring 2.5x3cms, localized between the celiac trunk and superior mesenteric artery in aortocaval location along with right ovarian cystic mass. A clinical diagnosis of malignant ovarian tumour with celiac nodal metastasis was made. Excision and pathological analysis of both revealed an aortocaval extra-adrenal paraganglioma and benign ovarian cyst. On serial follow-up the patient was in a good health, asymptomatic and without evidence of tumour recurrence. This case emphasizes the necessity of including extra-adrenal paraganglioma in the differential diagnosis and management of retroperitoneal tumours, despite its rarity.

  17. The cancer glycome: carbohydrates as mediators of metastasis.

    PubMed

    Glavey, Siobhan V; Huynh, Daisy; Reagan, Michaela R; Manier, Salomon; Moschetta, Michele; Kawano, Yawara; Roccaro, Aldo M; Ghobrial, Irene M; Joshi, Lokesh; O'Dwyer, Michael E

    2015-07-01

    Glycosylation is a frequent post-translational modification which results in the addition of carbohydrate determinants, "glycans", to cell surface proteins and lipids. These glycan structures form the "glycome" and play an integral role in cell-cell and cell-matrix interactions through modulation of adhesion and cell trafficking. Glycosylation is increasingly recognized as a modulator of the malignant phenotype of cancer cells, where the interaction between cells and the tumor micro-environment is altered to facilitate processes such as drug resistance and metastasis. Changes in glycosylation of cell surface adhesion molecules such as selectin ligands, integrins and mucins have been implicated in the pathogenesis of several solid and hematological malignancies, often with prognostic implications. In this review we focus on the functional significance of alterations in cancer cell glycosylation, in terms of cell adhesion, trafficking and the metastatic cascade and provide insights into the prognostic and therapeutic implications of recent findings in this fast-evolving niche.

  18. Predictive factors for lymph node metastasis in early gastric cancer

    PubMed Central

    Sung, Chang-Mu; Hsu, Chen-Ming; Hsu, Jun-Te; Yeh, Ta-Sen; Lin, Chun-Jung; Chen, Tse-Ching; Su, Ming-Yao; Chiu, Cheng-Tang

    2010-01-01

    AIM: To analyze the predictive factors for lymph node metastasis (LNM) in early gastric cancer (EGC). METHODS: Data from patients surgically treated for gastric cancers between January 1994 and December 2007 were retrospectively collected. Clinicopathological factors were analyzed to identify predictive factors for LNM. RESULTS: Of the 2936 patients who underwent gastrectomy and lymph node dissection, 556 were diagnosed with EGC and included in this study. Among these, 4.1% of patients had mucosal tumors (T1a) with LNM while 24.3% of patients had submucosal tumors with LNM. Univariate analysis found that female gender, tumors ≥ 2 cm, tumor invasion to the submucosa, vascular and lymphatic involvement were significantly associated with a higher rate of LNM. On multivariate analysis, tumor size, lymphatic involvement, and tumor with submucosal invasion were associated with LNM. CONCLUSION: Tumor with submucosal invasion, size ≥ 2 cm, and presence of lymphatic involvement are predictive factors for LNM in EGC. PMID:21049560

  19. Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis

    PubMed Central

    Jolly, Mohit Kumar; Boareto, Marcelo; Huang, Bin; Jia, Dongya; Lu, Mingyang; Ben-Jacob, Eshel; Onuchic, José N.; Levine, Herbert

    2015-01-01

    Transitions between epithelial and mesenchymal phenotypes – the epithelial to ­mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) – are hallmarks of cancer metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a “three-way” switch giving rise to three distinct phenotypes – E, M and hybrid E/M – and present a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity. Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell–cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs. These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype. Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies. Finally, we discuss the multiple advantages that the partial EMT or hybrid E/M phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary “bad actors” of metastasis. PMID:26258068

  20. Osteocytic Connexin Hemichannels Suppress Breast Cancer Growth and Bone Metastasis

    PubMed Central

    Zhou, Jade Z.; Riquelme, Manuel A.; Gu, Sumin; Kar, Rekha; Gao, Xiaoli; Sun, LuZhe; Jiang, Jean X.

    2016-01-01

    Although the skeleton is one of predominant sites for breast cancer metastasis, why breast cancer cells often become dormant after homing to bone is not well understood. Here, we reported an intrinsic self-defense mechanism of bone cells against breast cancer cells: a critical role of connexin (Cx) 43 hemichannels in osteocytes in the suppression of breast cancer bone metastasis. Cx43 hemichannels allow passage of small molecules between the intracellular and extracellular environments. The treatment of bisphosphonate drugs, either alendronate (ALN) or zoledronic acid (ZOL), opened Cx43 hemichannels in osteocytes. Conditioned media (CM) collected from MLO-Y4 osteocyte cells treated with bisphosphonates inhibited the anchorage-independent growth, migration and invasion of MDA-MB-231 human breast cancer cells and Py8119 mouse mammary carcinoma cells and this inhibitory effect was attenuated with Cx43(E2), a specific hemichannel blocking antibody. The opening of osteocytic Cx43 hemichannels by mechanical stimulation had similar inhibitory effects on breast cancer cells and this inhibition was attenuated by Cx43(E2) antibody as well. These inhibitory effects on cancer cells were mediated by ATP released from osteocyte Cx43 hemichannels. Furthermore, both Cx43 osteocyte-specific knockout mice and osteocyte-specific Δ130–136 transgenic mice with impaired Cx43 gap junctions and hemichannels showed significantly increased tumor growth and attenuated the inhibitory effect of ZOL. However, R76W transgenic mice with functional hemichannels but not gap junctions in osteocytes did not display a significant difference. Together, our studies establish the specific inhibitory role of osteocytic Cx43 hemichannels, and exploiting the activity of this channel could serve as a de novo therapeutic strategy. PMID:27041582

  1. Prostate cancer invasion and metastasis: insights from mining genomic data.

    PubMed

    Hudson, Bryan D; Kulp, Kristen S; Loots, Gabriela G

    2013-09-01

    Prostate cancer (PCa) is the second most commonly diagnosed malignancy in men in the Western world and the second leading cause of cancer-related deaths among men worldwide. Although most cancers have the potential to metastasize under appropriate conditions, PCa favors the skeleton as a primary site of metastasis, suggesting that the bone microenvironment is conducive to its growth. PCa metastasis proceeds through a complex series of molecular events that include angiogenesis at the site of the original tumor, local migration within the primary site, intravasation into the blood stream, survival within the circulation, extravasation of the tumor cells to the target organ and colonization of those cells within the new site. In turn, each one of these steps involves a complicated chain of events that utilize multiple protein-protein interactions, protein signaling cascades and transcriptional changes. Despite the urgent need to improve current biomarkers for diagnosis, prognosis and drug resistance, advances have been slow. Global gene expression methods such as gene microarrays and RNA sequencing enable the study of thousands of genes simultaneously and allow scientists to examine molecular pathways of cancer pathogenesis. In this review, we summarize the current literature that explored high-throughput transcriptome analysis toward the advancement of biomarker discovery for PCa. Novel biomarkers are strongly needed to enable more accurate detection of PCa, improve prediction of tumor aggressiveness and facilitate the discovery of new therapeutic targets for tailored medicine. Promising molecular markers identified from gene expression profiling studies include HPN, CLU1, WT1, WNT5A, AURKA and SPARC.

  2. Role of MTA1 in Cancer Progression and Metastasis

    PubMed Central

    Sen, Nirmalya; Gui, Bin; Kumar, Rakesh

    2014-01-01

    The MTA1 protein contributes to the process of cancer progression and metastasis through multiple genes and protein targets and interacting proteins with roles in transformation, anchorage-independent growth, invasion, survival, DNA-repair, angiogenesis, hormone-independence, metastasis and therapeutic resistance. MTA proteins control a spectrum of cancer promoting processes by modulating the expression of target genes and/or the activity of MTA-interacting proteins. In the case of MTA1, these functions are manifested through post-translational modifications of MTA1 in response to upstream signals, MTA1 interaction with binding proteins and the expression of target gene products. The MTA1 coregulator interacts with nucleosomes through modified histones and is an integrator of extracellular signaling and gene activator. Studies delineating the molecular basis of dual functionality of MTA1 reveal that the functions of MTA1-chromatin modifying complexes in the context of target gene regulation are dynamic in nature. The nature and targets of MTA1-chromatin modifying complexes are also governed by the dynamic plasticity of the nucleosome landscape as well as kinetics of activation and inactivation of enzymes responsible for post-translational modifications on the MTA1 protein. These broadly applicable functions also explain why MTA1 may be a ‘hub’ gene, whose current understanding is limited to selective influences on gene with roles in cancer but further research may reveal a more global influence. Because the deregulation of enzymes and their substrates with roles in MTA1-biology is not necessarily limited to cancer, we speculate that the lessons from MTA1 as a prototype dual master coregulator will be relevant for other human diseases. In this context, the concept of the dynamic nature of corepressor versus coactivator complexes and the MTA1 proteome as a function of time to signal is likely to be generally applicable to other multi-proteins regulatory complexes

  3. Toward decoding the principles of cancer metastasis circuits.

    PubMed

    Lu, Mingyang; Jolly, Mohit Kumar; Onuchic, Jose'; Ben-Jacob, Eshel

    2014-09-01

    Understanding epithelial-mesenchymal transitions (EMT) during cancer metastasis remains a major challenge in modern biology. Recent observations of cell behavior together with progress in mapping the underlying regulatory genetic networks led to new understandings of carcinoma metastasis. It is now established that the genetic network that regulates the EMT also enables an epithelial-mesenchymal hybrid phenotype. These hybrid cells possess mixed carcinoma epithelial and mesenchymal characteristics that enable specialized capabilities such as collective cell migration. On the gene network perspective, a four-component decision unit composed of two highly interconnected chimeric modules--the miR34/SNAIL and the miR200/ZEB mutual-inhibition feedback circuits--regulates the coexistence of and transitions between the different phenotypes. Here, we present a new tractable theoretical framework to model and decode the underlying principles governing the operation of the regulatory unit. Our approach connects the knowledge about intracellular pathways with observations of cellular behavior and advances toward understanding the logic of cancer decision-making. We found that the miR34/SNAIL module acts as an integrator while the miR200/ZEB module acts as a three-way switch. Consequently, the combined unit can give rise to three phenotypes (stable states): (i) a high miR200 and low ZEB, or (1, 0) state; (ii) a low miR200 and high ZEB, or (0, 1) state; and (iii) a medium miR200 and medium ZEB, or (½, ½) state. We associate these states with the epithelial, mesenchymal, and hybrid phenotypes, respectively. We reflect on the consistency between our theoretical predictions and recent observations in several types of carcinomas and suggest new testable predictions. See all articles in this Cancer Research section,

  4. Trefoil factor-3 expression in human colon cancer liver metastasis.

    PubMed

    Babyatsky, Mark; Lin, Jing; Yio, Xianyang; Chen, Anli; Zhang, Jie-yu; Zheng, Yan; Twyman, Christina; Bao, Xiuliang; Schwartz, Myron; Thung, Swan; Lawrence Werther, J; Itzkowitz, Steven

    2009-01-01

    Deaths from colorectal cancer are often due to liver metastasis. Trefoil factor-3 (TFF3) is expressed by normal intestinal epithelial cells and its expression is maintained throughout the colon adenoma-carcinoma sequence. Our previous work demonstrated a correlation between TFF3 expression and metastatic potential in an animal model of colon cancer. The aim of this study was to determine whether TFF3 is expressed in human colon cancer liver metastasis (CCLM) and whether inhibiting TFF3 expression in colon cancer cells would alter their invasive potential in vitro. Human CCLMs were analyzed at the mRNA and protein level for TFF3 expression. Two highly metastatic rat colon cancer cell lines that either natively express TFF3 (LN cells) or were transfected with TFF3 (LPCRI-2 cells), were treated with two rat TFF3 siRNA constructs (si78 and si365), and analyzed in an in vitro invasion assay. At the mRNA and protein level, TFF3 was expressed in 17/17 (100%) CCLMs and 10/11 (91%) primary colon cancers, but not in normal liver tissue. By real time PCR, TFF3 expression was markedly inhibited by both siRNA constructs in LN and LPCRI-2 cells. The si365 and si78 constructs inhibited invasion by 44% and 53%, respectively, in LN cells, and by 74% and 50%, respectively, in LPCRI-2 cells. These results provide further evidence that TFF3 contributes to the malignant behavior of colon cancer cells. These observations may have relevance for designing new diagnostic and treatment approaches to colorectal cancer.

  5. Melanoma Stem Cells and Metastasis: Mimicking Hematopoietic Cell Trafficking?

    PubMed Central

    Lee, Nayoung; Barthel, Steven R.; Schatton, Tobias

    2014-01-01

    Malignant melanoma is a highly metastatic cancer that bears responsibility for the majority of skin cancer-related deaths. Amidst the research efforts to better understand melanoma progression, there has been increasing evidence that hints at a role for a subpopulation of virulent cancer cells, termed malignant melanoma stem or initiating cells (MMICs), in metastasis formation. MMICs are characterized by their preferential ability to initiate and propagate tumor growth and their selective capacity for self-renewal and differentiation into less tumorigenic melanoma cells. The frequency of MMICs has been shown to correlate with poor clinical prognosis in melanoma. Additionally, MMICs are enriched among circulating tumor cells (CTCs) in the peripheral blood of cancer patients, suggesting that MMICs may be a critical player in the metastatic cascade. Although these links exist between MMICs and metastatic disease, the mechanisms by which MMICs may advance metastatic progression are only beginning to be elucidated. Recent studies have shown that MMICs express molecules critical for hematopoietic cell maintenance and trafficking, providing a possible explanation for how circulating MMICs could drive melanoma dissemination. We therefore propose that MMICs might fuel melanoma metastasis by exploiting homing mechanisms commonly utilized by hematopoietic cells. Here we review the biological properties of MMICs and the existing literature on their metastatic potential. We will discuss possible mechanisms by which MMICs might initiate metastases in the context of established knowledge of cancer stem cells (CSCs) in other cancers and of hematopoietic homing molecules, with a particular focus on selectins, integrins, chemokines, and chemokine receptors known to be expressed by melanoma cells. Biological understanding of how these molecules might be utilized by MMICs to propel the metastatic cascade could critically impact the development of more effective therapies for advanced

  6. Studying tumor metastasis by in vivo imaging and flow cytometer

    NASA Astrophysics Data System (ADS)

    Wei, Xunbin; Guo, Jin; Liu, Guangda; Li, Yan; Chen, Yun; Zhang, Li; Tan, Yuan; Chen, Tong; Gu, Zhenqin; Wang, Chen

    2009-02-01

    Liver cancer is one of the most common malignancies in the world, with approximately 1,000,000 cases reported every year. This ranges from 15,000 cases in the United States to more than a 250,000 in China. About 80% of people with primary liver cancer are male. Although two-thirds of people have advanced liver disease when they seek medical help, one third of the patients have cancer that has not progressed beyond the liver. Primary liver cancer (hepatocellular carcinoma, or HCC) is associated with liver cirrhosis 60-80% of the time. HCC may metastasize to the lung, bones, kidney, and many other organs. Surgical resection, liver transplantation, chemotherapy and radiation therapy are the foundation of current HCC therapies. However the outcomes are poor-the survival rate is almost zero for metastatic HCC patients. Molecular mechanisms of HCC metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of HCC cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern liver tumor cell spread through the microenvironment in vivo in real-time confocal near-infrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess liver tumor cell spreading and the circulation kinetics of liver tumor cells. A real-time quantitative monitoring of circulating liver tumor cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

  7. RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation.

    PubMed

    Morales, Mònica; Arenas, Enrique J; Urosevic, Jelena; Guiu, Marc; Fernández, Esther; Planet, Evarist; Fenwick, Robert Bryn; Fernández-Ruiz, Sonia; Salvatella, Xavier; Reverter, David; Carracedo, Arkaitz; Massagué, Joan; Gomis, Roger R

    2014-07-01

    In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme. PMID:24867881

  8. RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation

    PubMed Central

    Morales, Mònica; Arenas, Enrique J; Urosevic, Jelena; Guiu, Marc; Fernández, Esther; Planet, Evarist; Fenwick, Robert Bryn; Fernández-Ruiz, Sonia; Salvatella, Xavier; Reverter, David; Carracedo, Arkaitz; Massagué, Joan; Gomis, Roger R

    2014-01-01

    In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme. PMID:24867881

  9. Sorafenib for the treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a prospective multicenter cohort study.

    PubMed

    Nakano, Masahito; Tanaka, Masatoshi; Kuromatsu, Ryoko; Nagamatsu, Hiroaki; Tajiri, Nobuyoshi; Satani, Manabu; Niizeki, Takashi; Aino, Hajime; Okamura, Shusuke; Iwamoto, Hideki; Shimose, Shigeo; Shirono, Tomotake; Koga, Hironori; Torimura, Takuji

    2015-12-01

    Sorafenib, an oral multikinase inhibitor, is approved for advanced hepatocellular carcinoma (HCC) treatment. However, its therapeutic effect in advanced HCC patients with extrahepatic metastasis remains uncertain. This study aimed to prospectively assess the efficacy, safety, and survival risk factors and evaluate the prognostic impact of sorafenib treatment in advanced HCC patients with or without extrahepatic metastasis. Between May 2009 and March 2014, 312 consecutive advanced HCC patients who received sorafenib were enrolled in this study. We evaluated their characteristics and compared the clinical outcomes of those with and without extrahepatic metastasis. Of the enrolled patients, 245 (81%) received sorafenib treatment for more than 1 month, with a median duration of 3.6 months. Eighteen patients demonstrated partial response to sorafenib therapy, 127 had stable disease, and 134 had progressive disease at the first radiologic assessment. The median survival time (MST) and progression-free survival (PFS) were 10.3 and 3.6 months, respectively. Multivariate analysis identified gender, Child-Pugh class, baseline serum des-gamma-carboxy prothrombin level, and treatment duration as independent risk factors for survival. Extrahepatic metastasis was detected in 178 patients. However, the MST, PFS, and therapeutic effect were comparable between patients with and without extrahepatic metastasis. The independent risk factors for decreased overall survival in patients with extrahepatic metastasis were similar to those affecting all patients. Our results indicated that sorafenib could be administered for hepatic reserve and as long-term treatment for advanced HCC patients regardless of their extrahepatic metastasis status.

  10. Docosahexaenoic Acid Modulates Invasion and Metastasis of Human Ovarian Cancer via Multiple Molecular Pathways

    PubMed Central

    Wang, Ying-Chun; Wu, Yi-Nan; Wang, Su-Li; Lin, Qing-Hua; He, Ming-Fang; Liu, Qiao-lin; Wang, Jin-Hua

    2016-01-01

    Objective We investigated the effect of docosahexaenoic acid (DHA) on the invasion and metastasis of ovarian cancer cells (A2780, HO8910, and SKOV-3). Methods Cytotoxicity assay was performed to determine the optimal doses of DHA in this experiment. The effects of DHA on invasion ability were assessed by invasion assay. The expressions of messenger RNA and/or proteins associated with invasion or metastasis were detected by quantitative Real Time-Polymerase Chain Reaction or Western blot. The effect of DHA on cell metastasis was assessed in xenograft model of zebrafish. Results Docosahexaenoic acid and α-linolenic acid could reduce the cell vitalities in dose-dependent manner. However, DHA inhibited the invasion and metastasis of ovarian cancer cells, but α-linolenic acid did not (**P < 0.01). Docosahexaenoic acid could downregulate the expressions of WAVE3, vascular endothelial cell growth factor, and MMP-9, and upregulate KISS-1, TIMP-1, and PPAR-γ, which negatively correlated with cell invasion and metastasis (*P < 0.05). Docosahexaenoic acid restrained the development of subintestinal vessels and cancer cell metastasis in xenograft model of zebrafish (**P < 0.01). Conclusions Docosahexaenoic acid inhibited the invasion and metastasis of ovarian cancer cells in vitro and in vivo through the modulation of NF-κB signaling pathway, suggesting that DHA is a promising candidate for ovarian cancer therapy. PMID:27258728

  11. Differential secretome analysis reveals CST6 as a suppressor of breast cancer bone metastasis

    PubMed Central

    Jin, Lei; Zhang, Yan; Li, Hui; Yao, Ling; Fu, Da; Yao, Xuebiao; Xu, Lisa X; Hu, Xiaofang; Hu, Guohong

    2012-01-01

    Bone metastasis is a frequent complication of breast cancer and a common cause of morbidity and mortality from the disease. During metastasis secreted proteins play crucial roles in the interactions between cancer cells and host stroma. To characterize the secreted proteins that are associated with breast cancer bone metastasis, we preformed a label-free proteomic analysis to compare the secretomes of four MDA-MB-231 (MDA231) derivative cell lines with varied capacities of bone metastasis. A total of 128 proteins were found to be consistently up-/down-regulated in the conditioned medium of bone-tropic cancer cells. The enriched molecular functions of the altered proteins included receptor binding and peptidase inhibition. Through additional transcriptomic analyses of breast cancer cells, we selected cystatin E/M (CST6), a cysteine protease inhibitor down-regulated in bone-metastatic cells, for further functional studies. Our results showed that CST6 suppressed the proliferation, colony formation, migration and invasion of breast cancer cells. The suppressive function against cancer cell motility was carried out by cancer cell-derived soluble CST6. More importantly, ectopic expression of CST6 in cancer cells rescued mice from overt osteolytic metastasis and deaths in the animal study, while CST6 knockdown markedly enhanced cancer cell bone metastasis and shortened animal survival. Overall, our study provided a systemic secretome analysis of breast cancer bone tropism and established secreted CST6 as a bona fide suppressor of breast cancer osteolytic metastasis. PMID:22688893

  12. Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma.

    PubMed

    Wang, Cun; Jin, Guangzhi; Jin, Haojie; Wang, Ning; Luo, Qin; Zhang, Yurong; Gao, Dongmei; Jiang, Kai; Gu, Dishui; Shen, Qiujing; Huo, Xisong; Hu, Fangyuan; Ge, Tianxiang; Zhao, Fangyu; Chu, Wei; Shu, Huiqun; Yao, Ming; Cong, Wenming; Qin, Wenxin

    2015-02-20

    Clusterin (CLU) is a stress-induced chaperone that confers proliferative and survival advantages to cancer cells. However, effects and molecular mechanisms of CLU in hepatocellular carcinoma (HCC) metastasis are still unknown. In this study, HCC tissue array (n = 198) was utilized to investigate correlation between CLU expression and clinicopathological features. Overexpression of CLU in HCC tissues was correlated with shorter overall survival and higher tumor recurrence. In vitro and in vivo assays demonstrated that silencing CLU attenuated the invasion and metastasis of HCC cells, whereas ectopic overexpression of CLU resulted in the forced metastasis of HCC cells. We also revealed that CLU activated Akt signaling through complexing with eukaryotic translation initiation factor 3 subunit I (EIF3I), which in turn promoted matrix metalloproteinase 13 (MMP13) expression and HCC metastasis. Positive correlations between CLU and MMP13, p-Akt, or EIF3I were found in HCC tissues. We further observed that CLU knockdown using the CLU inhibitor OGX-011 significantly suppressed HCC metastasis in two metastatic models through inhibiting EIF3I/Akt/MMP13 signaling. These findings indicate that CLU is an independent predictive factor for prognosis of HCC and it facilitates metastasis through EIF3I/Akt/MMP13 signaling. CLU suppression using OGX-011 may represent a promising therapeutic option for suppressing HCC metastasis.

  13. Plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment.

    PubMed

    Li, Z; Xiao, J; Wu, X; Li, W; Yang, Z; Xie, J; Xu, L; Cai, X; Lin, Z; Guo, W; Luo, J; Liu, M

    2012-09-01

    Bone metastasis is a common and serious consequence of breast cancer. Bidirectional interaction between tumor cells and the bone marrow microenvironment drives a so-called 'vicious cycle' that promotes tumor cell malignancy and stimulates osteolysis. Targeting these interactions and pathways in the tumor-bone microenvironment has been an encouraging strategy for bone metastasis therapy. In the present study, we examined the effects of plumbagin on breast cancer bone metastasis. Our data indicated that plumbagin inhibited cancer cell migration and invasion, suppressed the expression of osteoclast-activating factors, altered the cancer cell induced RANKL/OPG ratio in osteoblasts, and blocked both cancer cell- and RANKL-stimulated osteoclastogenesis. In mouse model of bone metastasis, we further demonstrated that plumbagin significantly repressed breast cancer cell metastasis and osteolysis, inhibited cancer cell induced-osteoclastogenesis and the secretion of osteoclast-activating factors in vivo. At the molecular level, we found that plumbagin abrogated RANKL-induced NF-κB and MAPK pathways by blocking RANK association with TRAF6 in osteoclastogenesis, and by inhibiting the expression of osteoclast-activating factors through the suppression of NF-κB activity in breast cancer cells. Taken together, our data demonstrate that plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment and that plumbagin may serve as a novel agent in the treatment of tumor bone metastasis.

  14. Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization.

    PubMed

    Yang, M; Shao, J-H; Miao, Y-J; Cui, W; Qi, Y-F; Han, J-H; Lin, X; Du, J

    2014-08-01

    Macrophages are critical immune effector cells of the tumor microenvironment that promote seeding, extravasation and persistent growth of tumor cells in primary tumors and metastatic sites. Tumor progression and metastasis are affected by dynamic changes in the specific phenotypes of macrophage subpopulations; however, the mechanisms by which tumor cells modulate macrophage polarization remain incompletely understood. Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens. We report that increased CARD9 expression is primarily localized in infiltrated macrophages and significantly associated with advanced histopathologic stage and the presence of metastasis. Using CARD9-deficient (CARD9(-/-)) mice, we show that bone marrow-derived CARD9 promotes liver metastasis of colon carcinoma cells. Mechanistic studies reveal that CARD9 contributes to tumor metastasis by promoting metastasis-associated macrophage polarization through activation of the nuclear factor-kappa B signaling pathway. We further demonstrate that tumor cell-secreted vascular endothelial growth factor facilitates spleen tyrosine kinase activation in macrophages, which is necessary for formation of the CARD9-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 complex. Taken together, our results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis, thereby providing targets for anticancer therapies.

  15. Enhanced sonographic imaging to diagnose lymph node metastasis: importance of blood vessel volume and density.

    PubMed

    Li, Li; Mori, Shiro; Kodama, Mizuho; Sakamoto, Maya; Takahashi, Shoki; Kodama, Tetsuya

    2013-04-01

    Lymph node size is an important variable in ultrasound diagnosis of lymph node metastasis. However, the size criterion often leads to oversight of tumor-positive lymph nodes within the range of "normal" size, such that more accurate diagnostic criteria for lymph node metastasis are required. In this study, we show how diagnosis of lymph node metastasis can be improved by evaluating changes in blood vessel volume and density using a novel contrast-enhanced high-frequency ultrasound (CE-HFUS) system with Sonazoid. An MRL/MpJ-lpr/lpr (MRL/lpr) mouse model of lymph node metastasis was used in which lymph nodes are similar in size to humans. Metastasis via lymphatic vessels to proper axillary lymph nodes (proper ALN) was induced by injection of tumor cells into the subiliac lymph nodes. Within 21 days of injection, significant increases in blood vessel volume and density, but no increases in the size of the proper ALNs, were observed. The increase in blood vessel density was confirmed with immunohistochemical analysis and was positively related to tumor cell proliferation as measured using bioluminescence imaging. Together, our results showed that alterations in blood vessel volume and density precede alterations in lymph node size in the early stages of lymph node metastasis. Detection of these changes by ultrasonography may offer new criteria for early diagnosis of lymph node metastasis.

  16. Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model

    PubMed Central

    Chen, Xiaoyun; Wang, Jian; Cao, Ziquan; Hosaka, Kayoko; Jensen, Lasse; Yang, Huasheng; Sun, Yuping; Zhuang, Rujie; Liu, Yizhi; Cao, Yihai

    2015-01-01

    Retinoblastoma is a highly invasive malignant tumor that often invades the brain and metastasizes to distal organs through the blood stream. Invasiveness and metastasis of retinoblastoma can occur at the early stage of tumor development. However, an optimal preclinical model to study retinoblastoma invasiveness and metastasis in relation to drug treatment has not been developed. Here, we developed an orthotopic zebrafish model in which retinoblastoma invasion and metastasis can be monitored at a single cell level. We took the advantages of immune privilege and transparent nature of developing zebrafish embryos. Intravitreal implantation of color-coded retinoblastoma cells allowed us to kinetically monitor tumor cell invasion and metastasis. Further, interactions between retinoblastoma cells and surrounding microvasculatures were studied using a transgenic zebrafish that exhibited green fluorescent signals in blood vessels. We discovered that tumor cells invaded neighboring tissues and blood stream when primary tumors were at the microscopic sizes. These findings demonstrate that retinoblastoma metastasis occurs at the early stage and antiangiogenic drugs such as Vegf morpholino and sunitinib could potentially interfere with tumor invasiveness and metastasis. Thus, this orthotopic retinoblastoma model offers a new and unique opportunity to study the early events of tumor invasion, metastasis and drug responses. PMID:26169357

  17. Role of periostin and its antagonist PNDA-3 in gastric cancer metastasis.

    PubMed

    Liu, Guo-Xiao; Xi, Hong-Qing; Sun, Xiao-Yan; Wei, Bo

    2015-03-01

    The extracellular matrix component periostin is a secreted protein that functions as both a cell attachment protein and an autocrine or paracrine factor that signals through the cell adhesion molecule integrins αvβ3 and αvβ5. Periostin participates in normal physiological activities such as cardiac development, but is also involved in pathophysiological processes in vascular diseases, wound repair, bone formation, and tumor development. It is of increasing interest in tumor biology because it is frequently overexpressed in a variety of epithelial carcinomas and is functionally involved in multiple steps of metastasis progression. These include the maintenance of stemness, niche formation, EMT, the survival of tumor cells, and angiogenesis, all of which are indispensable for gastric cancer metastasis. Periostin has been reported to activate the PI-3K/AKT, Wnt, and FAK-mediated signaling pathways to promote metastasis. Therefore, periostin represents a potentially promising candidate for the inhibition of metastasis. In this review article, we summarize recent advances in knowledge concerning periostin, its antagonist PNDA-3, and their influence on such key processes in cancer metastasis as maintenance of stemness, niche formation, epithelial-to-mesenchymal transition, tumor cell survival, and angiogenesis. In particular, we focus our attention on the role of periostin in gastric cancer metastasis, speculate as to the usefulness of periostin as a therapeutic and diagnostic target for gastric cancer metastasis, and consider potential avenues for future research. PMID:25759527

  18. Mining metastasis related genes by primary-secondary tumor comparisons from large-scale databases

    PubMed Central

    Kim, Sangwoo; Lee, Doheon

    2009-01-01

    Background Metastasis is the most dangerous step in cancer progression and causes more than 90% of cancer death. Although many researchers have been working on biological features and characteristics of metastasis, most of its genetic level processes remain uncertain. Some studies succeeded in elucidating metastasis related genes and pathways, followed by predicting prognosis of cancer patients, but there still is a question whether the result genes or pathways contain enough information and noise features have been controlled appropriately. Methods We set four tumor type classes composed of various tumor characteristics such as tissue origin, cellular environment, and metastatic ability. We conducted a set of comparisons among the four tumor classes followed by searching for genes that are consistently up or down regulated through the whole comparisons. Results We identified four sets of genes that are consistently differently expressed in the comparisons, each of which denotes one of four cellular characteristics respectively – liver tissue, colon tissue, liver viability and metastasis characteristics. We found that our candidate genes for tissue specificity are consistent with the TiGER database. And we also found that the metastasis candidate genes from our method were more consistent with the known biological background and independent from other noise features. Conclusion We suggested a new method for identifying metastasis related genes from a large-scale database. The proposed method attempts to minimize the influences from other factors except metastatic ability including tissue originality and tissue viability by confining the result of metastasis unrelated test combinations. PMID:19344478

  19. RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation.

    PubMed

    Morales, Mònica; Arenas, Enrique J; Urosevic, Jelena; Guiu, Marc; Fernández, Esther; Planet, Evarist; Fenwick, Robert Bryn; Fernández-Ruiz, Sonia; Salvatella, Xavier; Reverter, David; Carracedo, Arkaitz; Massagué, Joan; Gomis, Roger R

    2014-05-27

    In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme.

  20. Increased metastasis with loss of E2F2 in Myc-driven tumors

    PubMed Central

    Yuwanita, Inez; Barnes, Danielle; Monterey, Michael D.; O'Reilly, Sandra; Andrechek, Eran R.

    2015-01-01

    In human breast cancer, mortality is associated with metastasis to distant sites. Therefore, it is critical to elucidate the biological mechanisms that underlie tumor progression and metastasis. Using signaling pathway signatures we previously predicted a role for E2F transcription factors in Myc induced tumors. To test this role we interbred MMTV-Myc transgenic mice with E2F knockouts. Surprisingly, we observed that the loss of E2F2 sharply increased the percentage of lung metastasis in MMTV-Myc transgenic mice. Examining the gene expression profile from these tumors, we identified genetic components that were potentially involved in mediating metastasis. These genes were filtered to uncover the genes involved in metastasis that also impacted distant metastasis free survival in human breast cancer. In order to elucidate the mechanism by which E2F2 loss enhanced metastasis we generated knockdowns of E2F2 in MDA-MB-231 cells and observed increased migration in vitro and increased lung colonization in vivo. We then examined genes that were differentially regulated between tumors from MMTV-Myc, MMTV-Myc E2F2−/−, and lung metastases samples and identified PTPRD. To test the role of PTPRD in E2F2-mediated breast cancer metastasis, we generated a knockdown of PTPRD in MDA-MB-231 cells. We noted that decreased levels of PTPRD resulted in decreased migration in vitro and decreased lung colonization in vivo. Taken together, these data indicate that E2F2 loss results in increased metastasis in breast cancer, potentially functioning through a PTPRD dependent mechanism. PMID:26474282

  1. Increased metastasis with loss of E2F2 in Myc-driven tumors.

    PubMed

    Yuwanita, Inez; Barnes, Danielle; Monterey, Michael D; O'Reilly, Sandra; Andrechek, Eran R

    2015-11-10

    In human breast cancer, mortality is associated with metastasis to distant sites. Therefore, it is critical to elucidate the biological mechanisms that underlie tumor progression and metastasis. Using signaling pathway signatures we previously predicted a role for E2F transcription factors in Myc induced tumors. To test this role we interbred MMTV-Myc transgenic mice with E2F knockouts. Surprisingly, we observed that the loss of E2F2 sharply increased the percentage of lung metastasis in MMTV-Myc transgenic mice. Examining the gene expression profile from these tumors, we identified genetic components that were potentially involved in mediating metastasis. These genes were filtered to uncover the genes involved in metastasis that also impacted distant metastasis free survival in human breast cancer. In order to elucidate the mechanism by which E2F2 loss enhanced metastasis we generated knockdowns of E2F2 in MDA-MB-231 cells and observed increased migration in vitro and increased lung colonization in vivo. We then examined genes that were differentially regulated between tumors from MMTV-Myc, MMTV-Myc E2F2-/-, and lung metastases samples and identified PTPRD. To test the role of PTPRD in E2F2-mediated breast cancer metastasis, we generated a knockdown of PTPRD in MDA-MB-231 cells. We noted that decreased levels of PTPRD resulted in decreased migration in vitro and decreased lung colonization in vivo. Taken together, these data indicate that E2F2 loss results in increased metastasis in breast cancer, potentially functioning through a PTPRD dependent mechanism.

  2. Loss of P53 facilitates invasion and metastasis of prostate cancer cells.

    PubMed

    Wang, Yi; Zhang, Y X; Kong, C Z; Zhang, Z; Zhu, Y Y

    2013-12-01

    Prostate cancer is a lethal cancer for the invasion and metastasis in its earlier period. P53 is a tumor suppressor gene which plays a critical role on safeguarding the integrity of genome. However, loss of P53 facilitates or inhibits the invasion and metastasis of tumor is still suspended. In this study, we are going to explain whether loss of P53 affect the invasion and metastasis of prostate cancer cells. To explore whether loss of P53 influences the invasion and metastasis ability of prostate cancer cells, we first compared the invasion ability of si-P53 treated cells and control cells by wound healing, transwell assay, and adhesion assay. We next tested the activity of MMP-2, MMP-9, and MMP-14 by western blot and gelatin zymography. Moreover, we employed WB and IF to identify the EMT containing E-cad, N-cad, vimentin, etc. We also examined the expression of cortactin, cytoskeleton, and paxillin by immunofluorescence, and tested the expression of ERK and JNK by WB. Finally, we applied WB to detect the expression of FAK, Src, and the phosphorylation of them to elucidate the mechanism of si-P53 influencing invasion and metastasis. According to the inhibition rate of si-P53, we choose the optimized volume of si-P53. With the volume, we compare the invasion and metastasis ability of Du145 and si-P53 treated cells. We find si-P53 promotes the invasion and metastasis in prostate cancer cells, increases the expression and activity of MMP-2/9 and MMP-14. Also, si-P53 promotes EMT and cytoskeleton rearrangement. Further analyses explain that this effect is associated with FAK-Src signaling pathway. Loss of P53 promotes the invasion and metastasis ability of prostate cancer cells and the mechanism is correlated with FAK-Src signaling pathway. P53 is involved in the context of invasion and metastasis. PMID:23982184

  3. Drug development against metastasis-related genes and their pathways: A rationale for cancer therapy

    PubMed Central

    Iiizumi, Megumi; Liu, Wen; Pai, Sudha K.; Furuta, Eiji; Watabe, Kounosuke

    2008-01-01

    It is well recognized that the majority of cancer related deaths is caused by metastatic disease. Therefore, there is an urgent need for the development of therapeutic intervention specifically targeted to the metastatic process. In the last decade, significant progress has been made in this research field, and many new concepts have emerged that shed light on the molecular mechanism of metastasis cascade which is often portrayed as a succession of six distinct steps; localized invasion, intravasation, translocation, extravasation, micrometastasis and colonization. Successful metastasis is dependent on the balance and complex interplay of both the metastasis promoters and suppressors in each step. Therefore, the basic strategy of our interventions is aimed at either blocking the promoters or potentiating the suppressors in this disease process. Toward this goal, various kinds of antibodies and small molecules have been designed. These include agents that block the ligand-recepter interaction of metastasis promoters (HGF/c-Met), antagonize the metastasis promoting enzymes (AMF,uPA and MMP) and inhibit the transcriptional activity of metastasis promoter (β-Catenin). On the other hand, the intriguing roles of metastasis suppressors and their signal pathways have been extensively studied and various attempts have been made to potentiate these factors. Small molecules have been developed to restore the expression or mimic the function of metastasis suppressor genes such as NM23, E-cadherin, Kiss-1, MKK4 and NDRG1, and some of them are under clinical trials. This review summarizes our current understanding of the molecular pathway of tumor metastasis and discusses strategies and recent development of anti-metastatic drugs. PMID:18692117

  4. The role of radiofrequency ablation for treatment of metachronous isolated hepatic metastasis from colorectal cancer.

    PubMed

    Lee, Byoung Chul; Lee, Hyun Gu; Park, In Ja; Kim, So Yeon; Kim, Ki-Hun; Lee, Jae Hoon; Kim, Chan Wook; Lee, Jong Lyul; Yoon, Yong Sik; Lim, Seok-Byung; Yu, Chang Sik; Kim, Jin Cheon

    2016-09-01

    We investigated recurrence pattern and oncologic outcomes after treatment of metachronous isolated liver metastases from colorectal cancer according to treatment modality.We retrospectively analyzed 123 patients treated with hepatic resection and 82 patients treated with radiofrequency ablation (RFA) for metachronous isolated hepatic metastasis from colorectal cancer (HMCRC). We compared clinicopathological data, recurrence pattern, and recurrence-free survival (RFS) rates after the treatment of hepatic metastasis between patients treated with RFA and resection.The patients in the 2 groups were similar in gender, location of primary tumor, disease-free interval to hepatic metastasis, pathologic stage of primary tumor, and number of hepatic metastasis. The age was older in RFA group but it was not statistically different. The mean diameter of the largest hepatic mass was greater in the resection group than in the RFA group (3.1 vs 1.9 cm, P < 0.001). Chemotherapy after the treatment of hepatic metastasis was more commonly given in hepatic resection group (76.4% vs 62.2%, P = 0.04). Recurrence after the treatment of hepatic metastasis was not significantly different between the 2 groups (54.5% vs 65.9% in the resection and RFA groups). However, intrahepatic recurrence without extra-hepatic metastases was more common in the RFA group than in the resection group (47.5% vs 12.1%, P < 0.001). The RFS rate after the treatment of hepatic metastasis was significantly higher in resection group (48.6% vs 33.7%, P = 0.015). The size and number of hepatic metastasis, primary tumor stage, disease-free interval to hepatic metastasis, and the modality of treatment (RFA vs resection) for hepatic metastasis were confirmed as associated factors with re-recurrence after the treatment of hepatic metastasis. Among patients with solitary hepatic metastases of ≤3 cm, marginal recurrence was higher in the RFA group (3% vs 17.2%) and re-RFA was performed to achieve comparable

  5. Epigenomic landscape of melanoma progression to brain metastasis: unexplored therapeutic alternatives.

    PubMed

    Marzese, Diego M; Witz, Isaac P; Kelly, Daniel F; Hoon, Dave S B

    2015-01-01

    Melanoma brain metastasis is a complication with rising incidence. Despite the high rate of somatic mutations driving the initial stages of melanocyte transformation, the brain colonization requires a phenotypic reprogramming that is, in part, influenced by epigenomic modifications. This special report summarizes recent findings in the epigenomic landscape of melanoma progression to brain metastasis, with particular emphasis on the clinical utility of DNA methylation, chromatin modifications and ncRNA expression as theragnostic markers, as well as the significance of the metastatic microenvironment on melanoma brain metastasis epigenome.

  6. A rare case of renal metastasis from squamous cell carcinoma of the cervix.

    PubMed

    Kulkarni, Maithili Mandar; Khandeparkar, Siddhi Gaurish Sinai; Joshi, Avinash R; Kothikar, Vishakha

    2016-01-01

    Cervical cancer is the most frequent type of cancer in women in many developing countries. Squamous cell carcinoma of the cervix spreads principally by lymphatics and less commonly through blood vessels. The most frequent sites for those who develop distant metastasis include lungs (21%), lumbar and thoracic spine (16%), and para-aortic lymph nodes (7%). Metastasis to the kidney is extremely rare with <10 previously reported cases. We report a case of renal metastasis from squamous cell carcinoma of the cervix detected in end-stage kidney due to hydronephrosis. PMID:27499599

  7. 18F-NaF PET/CT Images of Cardiac Metastasis From Osteosarcoma.

    PubMed

    Chou, Yi-Hsien; Ko, Kuan-Yin; Cheng, Mei-Fang; Chen, Wei-Wu; Yen, Ruoh-Fang

    2016-09-01

    Osteosarcomas are aggressive with a high incidence of recurrence and metastasis. Cardiac osteosarcoma metastasis is rare. We described a 17-year-old boy who had right distal femoral osteosarcoma with lung metastases. During follow-up, right ventricular (RV) metastasis was noted and confirmed by histopathological examination of the surgical specimen. F-NaF PET/CT was then arranged 1 month after debulking surgery for residual tumor survey. The images showed intense F-NaF uptake at RV region, suggestive of residual cardiac metastases.

  8. Adrenalectomy for solitary metastasis of Hepatocellular carcinoma post liver transplantation: Case report and literature review

    PubMed Central

    Jalbani, Imran Khan; Nazim, Syed M; Tariq, Muhammad Usman; Abbas, Farahat

    2016-01-01

    Liver transplantation (LT) is the treatment of choice for localized hepatocellular carcinoma (HCC) associated with cirrhosis. Extra hepatic metastasis is the most common cause of death in these patients. There is very little evidence regarding the natural history and treatment options for patients developing HCC recurrence after LT. Surgical resection offers a unique opportunity for solitary metastasis. We report a 61 year old male with solitary right adrenal metastasis 15 months post LT which was managed with open adrenalectomy. The patient is alive and disease free 24 months after the surgery. The case, histo-pathological findings and literature review is discussed. PMID:27648064

  9. Whistle from afar: a case of endotracheal metastasis in papillary thyroid cancer.

    PubMed

    Chattopadhyay, Bitoti; Bhattacharya, Biswamit; Chatterjee, Atri; Biswas, Pijush Kanti; Debnath, Nirod Baran

    2012-01-01

    Endotracheal metastasis is a rare situation, usually associated with malignancies of breast and gastrointestinal tract, specially colon. Papillary carcinoma of thyroid commonly disseminates through lymphatic channels and tracheal involvement through vascular route is rarely reported. Here, we report a case of tracheal metastasis from papillary carcinoma of thyroid. The patient responded to external beam radiation therapy with cobalt 60 beams in a dose of 44 Gy followed by a 16 Gy boost. The patient is under followup and is presently asymptomatic. This paper adds to the repertoire of evidence in treatment of endotracheal metastasis.

  10. Video-Assisted Thoracoscopic Surgery Lobectomy for Pulmonary Malignant Melanoma Metastasis

    PubMed Central

    Samancilar, Ozgur; Kaya, Seyda Ors; Akcay, Onur; Akcam, Tevfik Ilker; Ceylan, Kenan Can; Yener, Ali Galip

    2015-01-01

    Malign melanoma (MM) develops as a result of malign transformation of the melanocytes and constitutes 2–4% of all skin cancers, while being the most common cause of mortality among all skin cancers. In addition to other organs, distant organ metastases also include lung metastasis. A metastasectomy is an acceptable treatment option in cases of malign melanoma with isolated lung metastasis. The current report presents a case with isolated lung metastasis that underwent a right upper VATS (video-assisted thoracoscopic surgery) lobectomy due to tumour localization. PMID:26644775

  11. Adrenalectomy for solitary metastasis of Hepatocellular carcinoma post liver transplantation: Case report and literature review.

    PubMed

    Jalbani, Imran Khan; Nazim, Syed M; Tariq, Muhammad Usman; Abbas, Farahat

    2016-01-01

    Liver transplantation (LT) is the treatment of choice for localized hepatocellular carcinoma (HCC) associated with cirrhosis. Extra hepatic metastasis is the most common cause of death in these patients. There is very little evidence regarding the natural history and treatment options for patients developing HCC recurrence after LT. Surgical resection offers a unique opportunity for solitary metastasis. We report a 61 year old male with solitary right adrenal metastasis 15 months post LT which was managed with open adrenalectomy. The patient is alive and disease free 24 months after the surgery. The case, histo-pathological findings and literature review is discussed.

  12. Isolated Late Metastasis of a Renal Cell Cancer Treated by Radical Distal Pancreatectomy

    PubMed Central

    Baer, H.; Stenzl, A.; Czerniak, A.

    1996-01-01

    A 53–year-old man underwent right nephrectomy for a locally advanced renal cell carcinoma with concomitant resection of a solitary metastasis in the right lung. Ten years later, he presented with haematochezia caused by a tumour in the tail of pancreas, invading the transverse colon and the greater curvature of the stomach. The tumour was radically resected, and histological examination revealed a solitary metastasis of the previous renal cell carcinoma. This case illustrates a rare indication for pancreatic resection because of pancreatic metastasis. PMID:9187553

  13. Metastasis of breast cancer to renal cancer: report of a rare case.

    PubMed

    Huo, Zhijun; Gao, Yongsheng; Yu, Zhiyong; Zuo, Wenshu; Zhang, Yanfang

    2015-01-01

    Tumor-to-tumor metastasis (TTM) is a rare phenomenon. We present a case of an invasive ductal carcinoma (IDC) of the breast metastasizing to a clear cell renal cell carcinoma (RCC). Breast cancer (BC) metastasis to the RCC is rarely reported, especially in resected kidney tumor. In several cases reported, IDC was the exclusively histologic type of BC metastasized to RCC. It seems that the different molecular type of IDC doesn't affect the metastatic tendencies to RCC. TTM was an indicator of diffuse disease. For any patient with a history of breast cancer, especially with multi-organs metastasis, resection of kidney tumor should be carefully considered.

  14. 18F-NaF PET/CT Images of Cardiac Metastasis From Osteosarcoma.

    PubMed

    Chou, Yi-Hsien; Ko, Kuan-Yin; Cheng, Mei-Fang; Chen, Wei-Wu; Yen, Ruoh-Fang

    2016-09-01

    Osteosarcomas are aggressive with a high incidence of recurrence and metastasis. Cardiac osteosarcoma metastasis is rare. We described a 17-year-old boy who had right distal femoral osteosarcoma with lung metastases. During follow-up, right ventricular (RV) metastasis was noted and confirmed by histopathological examination of the surgical specimen. F-NaF PET/CT was then arranged 1 month after debulking surgery for residual tumor survey. The images showed intense F-NaF uptake at RV region, suggestive of residual cardiac metastases. PMID:27405028

  15. Spinal myxopapillary ependymoma with interval drop metastasis presenting as cauda equina syndrome: case report and review of literature

    PubMed Central

    Rege, Shrikant V.; Patil, Harshad; Songara, Abhishek

    2016-01-01

    Myxopapillary ependymoma is a benign slow-growing tumour, arising predominantly in the region of the filum terminale. It has been designated histologically as grade I neoplasm according to the 2007 WHO classification. Despite this benign character dissemination and metastasis along the cerebrospinal axis and metastasis to distant sites have occasionally been reported. There have been previously reported cases of drop metastasis from MPE, however in three of these cases the drop metastasis was diagnosed with concurrent primary spinal MPE. There has been only one previously published case of interval drop metastasis in a case of operated spinal MPE in literature. We hereby present the second case of interval drop metastasis in a case of conus MPE, with history of having undergone a subtotal resection and post operative adjuvant radiotherapy prior to second surgery. The patient presented months after the primary surgery with symptoms of cauda equina syndrome attributable to the drop metastasis. PMID:27757435

  16. Tumor vascularity and hematogenous metastasis in experimental murine intraocular melanoma.

    PubMed Central

    Grossniklaus, H E

    1998-01-01

    PURPOSE: The purpose of this study is to test the hypothesis that primary tumor vascularity in a murine model of intraocular melanoma positively correlates with the development and hematogenous spread of metastasis. METHODS: Forty 12-week-old C57BL6 mice were inoculated in either the anterior chamber (AC) or posterior compartment (PC) of 1 eye with 5 x 10(5) cells/microL of Queens tissue culture melanoma cells. The inoculated eye was enucleated at 2 weeks; the mice were sacrificed at 4 weeks postinoculation, and necropsies were performed. The enucleated eyes were examined for histologic and ultrastructural features, including relationship of tumor cells to tumor vascular channels, vascular pattern, and mean vascular density. RESULTS: Melanoma grew and was confined to the eye in 12 of 20 AC eyes and 10 of 20 PC eyes. Histologic and electron microscopic examination showed tumor invasion into vascular channels. Five of 12 AC tumors (42%) and 8 of 10 PC tumors (80%) metastasized. All of the AC tumors, but none of the PC tumors, that distantly metastasized also metastasized to ipsilateral cervical lymph nodes (P = .00535). There was no statistically significant difference of vascular pattern between the melanomas that did and did not metastasize to lungs in the PC group (P = .24), although there was a significant difference in the AC group (P = .02). Tumors with high-grade vascular patterns were more likely to metastasize than tumors with low-grade vascular patterns in the AC group. The mean vascular density positively correlated with the presence and number of metastases in both groups (P = .0000 and P < .001, respectively). There was no statistically significant difference of vascular pattern and mean vascular density for AC versus PC melanoma (P = .97). CONCLUSIONS: The rate of metastasis in this murine intraocular melanoma model positively correlates with primary tumor vascularity. The melanoma metastasizes via invasion of tumor vascular channels. AC melanoma also

  17. LCP nanoparticle for tumor and lymph node metastasis imaging

    NASA Astrophysics Data System (ADS)

    Tseng, Yu-Cheng

    A lipid/calcium/phosphate (LCP) nanoparticle formulation (particle diameter ˜25 nm) has previously been developed to delivery siRNA with superior efficiency. In this work, 111In was formulated into LCP nanoparticles to form 111In-LCP for SPECT/CT imaging. With necessary modifications and improvements of the LCP core-washing and surface-coating methods, 111In-LCP grafted with polyethylene glycol exhibited reduced uptake by the mononuclear phagocytic system. SPECT/CT imaging supported performed biodistribution studies, showing clear tumor images with accumulation of 8% or higher injected dose per gram tissue (ID/g) in subcutaneous, human-H460, lung-cancer xenograft and mouse-4T1, breast cancer metastasis models. Both the liver and the spleen accumulated ˜20% ID/g. Accumulation in the tumor was limited by the enhanced permeation and retention effect and was independent of the presence of a targeting ligand. A surprisingly high accumulation in the lymph nodes (˜70% ID/g) was observed. In the 4T1 lymph node metastasis model, the capability of intravenously injected 111In-LCP to visualize the size-enlarged and tumor-loaded sentinel lymph node was demonstrated. By analyzing the SPECT/CT images taken at different time points, the PK profiles of 111In-LCP in the blood and major organs were determined. The results indicated that the decrement of 111In-LCP blood concentration was not due to excretion, but to tissue penetration, leading to lymphatic accumulation. Larger LCP (diameter ˜65 nm) nanoparticles were also prepared for the purpose of comparison. Results indicated that larger LCP achieved slightly lower accumulation in the tumor and lymph nodes, but much higher accumulation in the liver and spleen; thus, larger nanoparticles might not be favorable for imaging purposes. We also demonstrated that LCP with a diameter of ˜25 nm were better able to penetrate into tissues, travel in the lymphatic system and preferentially accumulate in the lymph nodes due to 1) small

  18. Gastric Metastasis of Hepatocellular Carcinoma With Gastrointestinal Bleeding After Liver Transplant: A Case Report.

    PubMed

    Li, L; Zhang, W H; Meng, F P; Ma, X M; Shen, L J; Jin, B; Li, H W; Han, J; Zhou, G D; Liu, S H

    2015-10-01

    Gastrointestinal (GI) metastasis of hepatocellular carcinoma is very rare. This is the first report of post-transplantation gastric metastasis. A 43-year-old man with a history of hepatitis B-related hepatocellular carcinoma (HCC) in the right anterior segment of the liver received an orthotopic liver transplant. Three months after the transplantation, pulmonary metastasis was found by chest computed tomography, and he received 1 course of gamma knife treatment. He complained of melena with anemia 17 months post liver transplantation. Abdominal CT scan showed new occupying lesions in the liver and a mass in the stomach and around the spleen with embolus in the splenic vein. Endoscopy revealed a large irregular cauliflower-like mass in fundus with ulceration and bleeding on the surface. He received symptomatic treatment, but died of cancer-related bleeding 4 months later. GI bleeding may due to gastric metastasis after liver transplantation. PMID:26518968

  19. Searching early bone metastasis on plain radiography by using digital imaging processing

    NASA Astrophysics Data System (ADS)

    Jaramillo-Núñez, A.; Pérez-Meza, M.

    2012-10-01

    Some authors mention that it is not possible to detect early bone metastasis on plain radiography. In this work we use digital imaging processing to analyze three radiographs taken from a patient with bone metastasis discomfort on the right shoulder. The time period among the first and second radiography was approximately one month and between the first and the third one year. This procedure is a first approach in order to know if in this particular case it was possible to detect an early bone metastasis. The obtained results suggest that by carrying out a digital processing is possible to detect the metastasis since the radiography contains the information although visually it is not possible to observe it.

  20. Searching early bone metastasis on plain radiography by using digital imaging processing

    SciTech Connect

    Jaramillo-Nunez, A.; Perez-Meza, M.

    2012-10-23

    Some authors mention that it is not possible to detect early bone metastasis on plain radiography. In this work we use digital imaging processing to analyze three radiographs taken from a patient with bone metastasis discomfort on the right shoulder. The time period among the first and second radiography was approximately one month and between the first and the third one year. This procedure is a first approach in order to know if in this particular case it was possible to detect an early bone metastasis. The obtained results suggest that by carrying out a digital processing is possible to detect the metastasis since the radiography contains the information although visually it is not possible to observe it.

  1. Quantitative protein profiling of tumor angiogenesis and metastasis biomarkers in mouse and human models

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tumor and stromal cells secrete a variety of proteins acting as extracellular signals and creating a supportive microenvironment for tumor development, angiogenesis, and metastasis. We used the Luminex immunoassay platform (including MILLIPLEX® MAP cytokine/chemokine, bone metabolism, adipocyte, M...

  2. Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes.

    PubMed

    Han, Yo-Han; Kee, Ji-Ye; Kim, Dae-Seung; Mun, Jeong-Geon; Jeong, Mi-Young; Park, Sang-Hyun; Choi, Byung-Min; Park, Sung-Joo; Kim, Hyun-Jung; Um, Jae-Young; Hong, Seung-Heon

    2016-08-27

    Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

  3. A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis.

    PubMed

    Adorno, Maddalena; Cordenonsi, Michelangelo; Montagner, Marco; Dupont, Sirio; Wong, Christine; Hann, Byron; Solari, Aldo; Bobisse, Sara; Rondina, Maria Beatrice; Guzzardo, Vincenza; Parenti, Anna R; Rosato, Antonio; Bicciato, Silvio; Balmain, Allan; Piccolo, Stefano

    2009-04-01

    TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.

  4. The Italian cross-sectional survey of the management of bone metastasis: ZeTa study

    PubMed Central

    Santini, Daniele; Bertoldo, Francesco; Dell'Aquila, Emanuela; Cecchini, Isabella; Fregosi, Stefania; Bortolussi, Paolo

    2012-01-01

    Background Several studies have emphasized the importance of the maintenance of bone health in a comprehensive cancer care. However, no survey about approach to bone metastasis care is currently available. The ZeTa study provides a picture of the Italian oncologists' therapeutics habits in this area, in a real clinical-practice scenario. Design This study was based on online questionnaire-based interviews to Italian oncologists that included 145 questions. The aim was to collect information on the treatment of bone metastasis, the current use of bisphosphonates, the awareness of guidelines and the concerns about ONJ, the use of vitamin D supplementation. Results 445 oncologists were contacted, 283 agreed to participate. The results show that the current management of bone metastasis is still sub-optimal, as the recommendations from current clinical guidelines are not completely followed by all specialists. Conclusions This survey highlights the urgent need to improve management of bone metastasis in cancer patients. PMID:26909253

  5. Current Approaches of Photothermal Therapy in Treating Cancer Metastasis with Nanotherapeutics

    PubMed Central

    Zou, Lili; Wang, Hong; He, Bin; Zeng, Lijuan; Tan, Tao; Cao, Haiqiang; He, Xinyu; Zhang, Zhiwen; Guo, Shengrong; Li, Yaping

    2016-01-01

    Cancer metastasis accounts for the high mortality of many types of cancer. Owing to the unique advantages of high specificity and minimal invasiveness, photothermal therapy (PTT) has been evidenced with great potential in treating cancer metastasis. In this review, we outline the current approaches of PTT with respect to its application in treating metastatic cancer. PTT can be used alone, guided with multimodal imaging, or combined with the current available therapies for effective treatment of cancer metastasis. Numerous types of photothermal nanotherapeutics (PTN) have been developed with encouraging therapeutic efficacy on metastatic cancer in many preclinical animal experiments. We summarize the design and performance of various PTN in PTT alone and their combinational therapy. We also point out the lacking area and the most promising approaches in this challenging field. In conclusion, PTT or their combinational therapy can provide an essential promising therapeutic modality against cancer metastasis. PMID:27162548

  6. Jejunal intussusception caused by metastasis of a giant cell carcinoma of the lung

    PubMed Central

    Fujii, Yuki; Homma, Shigenori; Yoshida, Tadashi; Taketomi, Akinobu

    2016-01-01

    A 55-year-old woman was admitted to our hospital reporting of nausea, vomiting and anorexia. One month before admission, she had been diagnosed with lung cancer with intestinal metastasis. A CT scan confirmed intussusception due to intestinal metastasis and she underwent emergency laparoscopic surgery followed by resection of the primary lung cancer. Histopathological findings of the intestinal specimen suggested the metastasis was from a giant cell carcinoma of the lung, which had extensive necrosis. She was still alive without recurrence 11 months after the first surgery. Giant cell carcinoma of the lung is a rare type of non-small cell carcinoma and intestinal metastasis is one of the unique features. This type of tumour has such aggressive characteristics that oncological prognosis is reported to be extremely poor. In our case, however, complete surgical resection of both primary and metastatic tumours might result in a better outcome than has been reported. PMID:27485876

  7. Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes.

    PubMed

    Han, Yo-Han; Kee, Ji-Ye; Kim, Dae-Seung; Mun, Jeong-Geon; Jeong, Mi-Young; Park, Sang-Hyun; Choi, Byung-Min; Park, Sung-Joo; Kim, Hyun-Jung; Um, Jae-Young; Hong, Seung-Heon

    2016-01-01

    Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis. PMID:27618887

  8. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan

    PubMed Central

    Maishi, Nako; Ohba, Yusuke; Akiyama, Kosuke; Ohga, Noritaka; Hamada, Jun-ichi; Nagao-Kitamoto, Hiroko; Alam, Mohammad Towfik; Yamamoto, Kazuyuki; Kawamoto, Taisuke; Inoue, Nobuo; Taketomi, Akinobu; Shindoh, Masanobu; Hida, Yasuhiro; Hida, Kyoko

    2016-01-01

    Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal–regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis. PMID:27295191

  9. MicroRNAs: promising biomarkers for diagnosis and therapeutic targets in human colorectal cancer metastasis.

    PubMed

    Hur, Keun

    2015-04-01

    Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Distant metastasis is a major cause of mortality in CRC. MicroRNAs (miRNAs) are small non-coding RNA molecules involved in the post-transcriptional and translational regulation of gene expression. Many miRNAs are aberrantly expressed in cancer and influence tumor progression. Accumulating studies suggest that multiple miRNAs are actively involved in the CRC metastasis process. Thus, we aim to introduce the role of miRNAs in multi-steps of CRC metastasis, including cancer cell invasion, intravasation, circulation, extravasation, colonization, angiogenesis, and epithelial-mesenchymal transition (EMT). Moreover, we suggest the potential application of miRNAs as biomarkers for CRC patients with metastasis.

  10. Gastric Metastasis of Hepatocellular Carcinoma With Gastrointestinal Bleeding After Liver Transplant: A Case Report.

    PubMed

    Li, L; Zhang, W H; Meng, F P; Ma, X M; Shen, L J; Jin, B; Li, H W; Han, J; Zhou, G D; Liu, S H

    2015-10-01

    Gastrointestinal (GI) metastasis of hepatocellular carcinoma is very rare. This is the first report of post-transplantation gastric metastasis. A 43-year-old man with a history of hepatitis B-related hepatocellular carcinoma (HCC) in the right anterior segment of the liver received an orthotopic liver transplant. Three months after the transplantation, pulmonary metastasis was found by chest computed tomography, and he received 1 course of gamma knife treatment. He complained of melena with anemia 17 months post liver transplantation. Abdominal CT scan showed new occupying lesions in the liver and a mass in the stomach and around the spleen with embolus in the splenic vein. Endoscopy revealed a large irregular cauliflower-like mass in fundus with ulceration and bleeding on the surface. He received symptomatic treatment, but died of cancer-related bleeding 4 months later. GI bleeding may due to gastric metastasis after liver transplantation.

  11. Isolated bony metastasis to upper limb from carcinoma of the oesophagus: report of three cases.

    PubMed

    Purkayastha, Joydeep

    2015-03-01

    Carcinoma of the oesophagus metastasizes to distant sites in approximately one third of cases and rarely involves the upper limb bones. We describe three such rare cases of isolated metastasis to upper limb bone from oesophageal cancer. PMID:25762887

  12. Small cell lung cancer with metastasis to the thyroid in a patient with toxic multinodular goiter.

    PubMed

    Ozgu, Eylem Sercan; Gen, Ramazan; Ilvan, Ahmet; Ozge, Cengiz; Polat, Ayşe; Vayisoglu, Yusuf

    2012-11-01

    Thyroid metastasis of lung cancer is rarely observed in clinical practice. The primary cancers which metastasize to the thyroid gland are mostly renal cell carcinoma, lung cancer, and breast cancer. Transient destructive thyrotoxicosis is caused by massive metastasis of extrathyroid tumors. We herein present a case report of a patient with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. A 66-year-old man complained of swelling around the right side of the neck, dyspnea, progressive weight loss, and palpitation starting since 3 months before his admission. The patient was diagnosed with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. The case report presented here illustrates the challenge of making a definitive and adequate diagnosis, particularly if the patient presents with 2 potential causes of thyrotoxicosis. Thyroid scintigraphy is an important tool for differential diagnosis of thyrotoxicosis. PMID:23172496

  13. RASSF8 downregulation promotes lymphangiogenesis and metastasis in esophageal squamous cell carcinoma

    PubMed Central

    Huang, Shu-Ting; Xu, Jing; Yuan, Lin-Jing; Huang, Long; Zhou, Yun; Yu, Xing-Juan; Wu, Shao-Yun; Luo, Rong-Zhen; Yun, Jing-Ping; Jia, Wei-Hua; Zheng, Min

    2015-01-01

    Lymphatic vessels are the major routes of human esophageal squamous cell carcinoma (ESCC) metastasis. Tumor cells secrete pro-lymphangiogenic factors to induce new lymphatic vessels, promoting lymph node metastasis. In this study, we show that RAS association domain family 8 (RASSF8) expression in ESCC clinical samples was inversely correlated with lymph node metastasis and patients survival. Tumor cells with low RASSF8 expression had higher apparent migratory ability, and promoted and lymphangiogenesis both in vitro and in vivo. RASSF8 downregulation enhanced VEGF-C expression and caused subcellular redistribution of p65 in ESCC. Our results show that RASSF8 acts as a tumor suppressor in ESCC and is a potential therapeutic target for preventing lymph node metastasis. PMID:26439687

  14. Temporal Characterization of Lymphatic Metastasis in an Orthotopic Mouse Model of Oral Cancer

    PubMed Central

    Szaniszlo, Peter; Fennewald, Susan M.; Qiu, Suimin; Kantara, Carla; Shilagard, Tuya; Vargas, Gracie; Resto, Vicente A.

    2013-01-01

    Background Overall mortality rate of head and neck squamous cell carcinoma (HNSCC) has not improved over the past 30 years; mostly due to high treatment failure rate among patients with regionally metastatic disease. To better understand the pathobiological processes leading to lymphatic metastasis development there is an urgent need for relevant animal models. Methods HNSCC cell lines were implanted into the tongues of athymic, nude mice. Histology, immunohistochemistry and ex vivo two-photon microscopy were used to evaluate tumor progress and spread. Results Orthotopic xenografts of different HNSCC cell lines produced distinct patterns of survival, tumor histology, disease progression rate, and lymph node metastasis development. Remarkably, all injected cell types reached the lymph nodes within 24 hours after injection, but not all developed metastasis. Conclusions This orthotopic xenograft model closely mimics several characteristics of human cancer and could be extremely valuable for translational studies focusing on lymphatic metastasis development and pathobiology. PMID:24115017

  15. Cutaneous Metastasis of Neuroendocrine Carcinoma with Unknown Primary Site: Case Report and Review of the Literature

    PubMed Central

    Amorim, Gustavo Moreira; Quintella, Danielle; Cuzzi, Tullia; Rodrigues, Rosangela; Ramos-e-Silva, Marcia

    2015-01-01

    We report a new case of neuroendocrine carcinoma for which it was not possible to find the primary site until now. The recent medical literature about skin metastasis of neuroendocrine carcinoma (neuroendocrine tumor) is discussed. PMID:26557073

  16. Jejunal intussusception caused by metastasis of a giant cell carcinoma of the lung.

    PubMed

    Fujii, Yuki; Homma, Shigenori; Yoshida, Tadashi; Taketomi, Akinobu

    2016-01-01

    A 55-year-old woman was admitted to our hospital reporting of nausea, vomiting and anorexia. One month before admission, she had been diagnosed with lung cancer with intestinal metastasis. A CT scan confirmed intussusception due to intestinal metastasis and she underwent emergency laparoscopic surgery followed by resection of the primary lung cancer. Histopathological findings of the intestinal specimen suggested the metastasis was from a giant cell carcinoma of the lung, which had extensive necrosis. She was still alive without recurrence 11 months after the first surgery. Giant cell carcinoma of the lung is a rare type of non-small cell carcinoma and intestinal metastasis is one of the unique features. This type of tumour has such aggressive characteristics that oncological prognosis is reported to be extremely poor. In our case, however, complete surgical resection of both primary and metastatic tumours might result in a better outcome than has been reported. PMID:27485876

  17. Serpins promote cancer cell survival and vascular co-option in brain metastasis.

    PubMed

    Valiente, Manuel; Obenauf, Anna C; Jin, Xin; Chen, Qing; Zhang, Xiang H-F; Lee, Derek J; Chaft, Jamie E; Kris, Mark G; Huse, Jason T; Brogi, Edi; Massagué, Joan

    2014-02-27

    Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

  18. Pathogenesis of Breast Cancer Metastasis to Brain: a Comprehensive Approach to the Signaling Network.

    PubMed

    Tayyeb, Bahrami; Parvin, Mehdipour

    2016-01-01

    There is a general consensus that breast cancer is a rising trend disease in the world. It is one of the most common cancer types and is the leading cause of death among women's cancers. There are several reasons for this high rate of mortality including metastasis which is responsible for about 90 % of cancer-related mortality. Therefore, recognition and understanding of metastatic process is important, and by considering the key role of pathophysiological route in metastasis as a multistep cascade of "invasion-metastasis," it might modify and improve our insight toward this complex phenomenon. Moreover, it can provide novel approaches for designing advanced targeted therapies. The present work aimed to review the published papers regarding molecular basis of metastatic process of breast cancer to brain metastasis, especially related genes and signaling network. Furthermore, the use of molecular aspects of metastatic breast cancer to brain was discussed in horizon of future treatment of breast cancer.

  19. [New thoughts are needed for the study of liver cancer recurrence and metastasis].

    PubMed

    Tang, Z Y

    2016-05-20

    In the recent years, our knowledge on cancer and metastasis has been renewed, and therefore new thoughts are needed for the study of cancer metastasis. Based on the fact that cancer is a systemic and dynamic disease which is caused by multiple factors, involves various genes, and has multiple stages, more studies should be conducted in the following aspects: (1) intervention of cancer metastasis; (2) systemic intervention focusing on the nervous system, immune status, endocrine, and metabolism; (3) studies on improving residual cancer and microenvironment; (4) studies on multimodality therapy, especially the combination of eradication and modification; (5) dynamic studies on cancer metastasis, especially the intervention leading to increased metastatic potential after tumor eradication. PMID:27470881

  20. Weighted gene co-expression network analysis of colorectal cancer liver metastasis genome sequencing data and screening of anti-metastasis drugs.

    PubMed

    Gao, Bo; Shao, Qin; Choudhry, Hani; Marcus, Victoria; Dong, Kung; Ragoussis, Jiannis; Gao, Zu-Hua

    2016-09-01

    Approximately 9% of cancer-related deaths are caused by colorectal cancer (CRC). CRC patients are prone to liver metastasis, which is the most important cause for the high CRC mortality rate. Understanding the molecular mechanism of CRC liver metastasis could help us to find novel targets for the effective treatment of this deadly disease. Using weighted gene co-expression network analysis on the sequencing data of CRC with and with metastasis, we identified 5 colorectal cancer liver metastasis related modules which were labeled as brown, blue, grey, yellow and turquoise. In the brown module, which represents the metastatic tumor in the liver, gene ontology (GO) analysis revealed functions including the G-protein coupled receptor protein signaling pathway, epithelial cell differentiation and cell surface receptor linked signal transduction. In the blue module, which represents the primary CRC that has metastasized, GO analysis showed that the genes were mainly enriched in GO terms including G-protein coupled receptor protein signaling pathway, cell surface receptor linked signal transduction, and negative regulation of cell differentiation. In the yellow and turquoise modules, which represent the primary non-metastatic CRC, 13 downregulated CRC liver metastasis-related candidate miRNAs were identified (e.g. hsa-miR-204, hsa-miR-455, etc.). Furthermore, analyzing the DrugBank database and mining the literature identified 25 and 12 candidate drugs that could potentially block the metastatic processes of the primary tumor and inhibit the progression of metastatic tumors in the liver, respectively. Data generated from this study not only furthers our understanding of the genetic alterations that drive the metastatic process, but also guides the development of molecular-targeted therapy of colorectal cancer liver metastasis. PMID:27571956

  1. Weighted gene co-expression network analysis of colorectal cancer liver metastasis genome sequencing data and screening of anti-metastasis drugs.

    PubMed

    Gao, Bo; Shao, Qin; Choudhry, Hani; Marcus, Victoria; Dong, Kung; Ragoussis, Jiannis; Gao, Zu-Hua

    2016-09-01

    Approximately 9% of cancer-related deaths are caused by colorectal cancer (CRC). CRC patients are prone to liver metastasis, which is the most important cause for the high CRC mortality rate. Understanding the molecular mechanism of CRC liver metastasis could help us to find novel targets for the effective treatment of this deadly disease. Using weighted gene co-expression network analysis on the sequencing data of CRC with and with metastasis, we identified 5 colorectal cancer liver metastasis related modules which were labeled as brown, blue, grey, yellow and turquoise. In the brown module, which represents the metastatic tumor in the liver, gene ontology (GO) analysis revealed functions including the G-protein coupled receptor protein signaling pathway, epithelial cell differentiation and cell surface receptor linked signal transduction. In the blue module, which represents the primary CRC that has metastasized, GO analysis showed that the genes were mainly enriched in GO terms including G-protein coupled receptor protein signaling pathway, cell surface receptor linked signal transduction, and negative regulation of cell differentiation. In the yellow and turquoise modules, which represent the primary non-metastatic CRC, 13 downregulated CRC liver metastasis-related candidate miRNAs were identified (e.g. hsa-miR-204, hsa-miR-455, etc.). Furthermore, analyzing the DrugBank database and mining the literature identified 25 and 12 candidate drugs that could potentially block the metastatic processes of the primary tumor and inhibit the progression of metastatic tumors in the liver, respectively. Data generated from this study not only furthers our understanding of the genetic alterations that drive the metastatic process, but also guides the development of molecular-targeted therapy of colorectal cancer liver metastasis.

  2. Palliative Surgery for Rare Cases of Anterior Urethral Metastasis in Prostate Cancer

    PubMed Central

    Gómez Gómez, Enrique; Carrasco Aznar, Jose Carlos; Moreno Rodríguez, Maria del Mar; Valero Rosa, José; Requena Tapia, Maria José

    2014-01-01

    Penis metastasis from prostate cancer is very rare, and its management varies from case to case as there are very few cases reported in the literature. We describe a patient with prostate cancer treated with radiotherapy and androgen deprivation therapy who presented with urethral bleeding as a symptom of anterior urethral metastasis during followup. We propose a way to manage this and review the literature. PMID:25161796

  3. Breast metastasis from recurrent gallbladder adenocarcinoma: a case report with review of the literature.

    PubMed

    Amarti, Lamiae El; Faouzi, Houssin; Salmi, Nariman; Ettahri, Hamza; Elghissassi, Ibrahim; Mrabti, Hind; Errihani, Hassan

    2016-08-01

    Gallbladder adenocarcinoma has a poor prognostic. The leading modes of dissemination in gallbladder cancer (GBC) are lymphatic, vascular, neural, intraperitoneal, and intraductal. The most common site of dissemination is liver. Breast metastasis in GBC is an unusual site of dissemination. Only few cases have been reported in the literature. We report a rare case of solitary breast metastasis from recurrent gallbladder carcinoma in light of existing literature. PMID:27512606

  4. Overexpression of p28GANK accelerates the metastasis of oesophageal squamous cell carcinoma.

    PubMed

    Tang, Shanhong; Qin, Jianping; Liu, Weihui; Zheng, Xiushan; Wu, Xiaoling; Xu, Hui; Qiao, Lijuan; Fan, Quanshui; Zeng, Weizheng; Jiang, Mingde

    2015-06-01

    The present study aimed to evaluate the effects of p28GANK expression on the metastasis of oesophageal squamous cell carcinoma (ESCC) tissues and to investigate its roles in the metastasis of highly invasive and non‑invasive ESCC cell lines. Quantitative polymerase chain reaction (qPCR) and immunohistochemical analyses were performed to assess p28GANK mRNA and protein expression in ESCC tissues and to analyse its significance in ESCC metastasis. qPCR and western blot analyses were used to detect p28GANK mRNA and protein expression in highly invasive and non‑invasive cell lines. Subsequently, lentivirus‑mediated p28GANK short interfering RNA (siRNA) was transfected into highly invasive ESCC cells, and Transwell assays were performed to analyse the effects of p28GANK knockdown on their migration and invasion. The mean expression levels of p28GANK mRNA in the ESCC tissues of patients with metastasis were significantly higher than those in the ESCC specimens from patients without metastasis. p28GANK expression in ESCC tissues was correlated with T‑stage, lymph node metastasis and lymphatic invasion. The mRNA and protein expression levels of p28GANK were significantly higher in highly invasive cell lines compared with those of matched, non‑invasive cell lines. Lentivirus‑mediated siRNA knockdown of p28GANK markedly decreased p28GANK expression in EC109‑P and EC9706‑P cells and supressed the metastasis of ESCC cells in vitro. In conclusion, p28GANK expression was increased in metastatic ESCC tissues and cells, and p28GANK knockdown decreased the metastatic ability of ESCC cells. These results suggested that p28GANK may be a potential therapeutic marker for ESCC metastasis.

  5. Histologic Features of Conjunctival Melanoma Predictive of Metastasis and Death (An American Ophthalmological Thesis)

    PubMed Central

    Esmaeli, Bita; Roberts, Dianna; Ross, Merrick; Fellman, Melissa; Cruz, Hilda; Kim, Stella K.; Prieto, Victor G.

    2012-01-01

    Purpose: In conjunctival melanoma, tumor thickness and nonlimbal location are associated with poor prognosis. However, other established high-risk features for cutaneous melanoma, including ulceration, mitotic figures, epithelioid cell type, and lymphovascular invasion, have not previously been studied extensively for their prognostic value in conjunctival melanoma. We examined the hypothesis that these features also predict regional nodal metastasis and death in conjunctival melanoma. Methods: The medical records of 44 of 46 consecutive conjunctival melanoma patients treated between June 2003 and December 2009 were retrospectively reviewed; tumor tissue was not available for the two excluded patients. Demographic and clinicopathologic features, including tumor location, tumor thickness, ulceration, mitotic rate, histology, lymphovascular invasion, and microsatellitosis, were reviewed. Outcome measures included regional nodal metastasis, distant metastasis, and death. Results: Twenty-six women and 18 men had a median age of 62 years. Regional nodal metastasis occurred in 7 patients (16%) and distant metastasis in 9 (20%). Median follow-up was 40 months. At last follow-up, 10 patients (23%) had died of disease. Tumor thickness >2.0 mm, ulceration, and mitotic figure >1/mm2 predicted regional nodal metastasis and death from disease. In addition to these three histologic features, vascular invasion, epithelioid cell type, and microsatellitosis significantly predicted death from disease. Tumor location (bulbar vs nonbulbar) was not correlated with regional nodal metastasis or death. Conclusions: In conjunctival melanoma, as in cutaneous melanoma, thicker tumor, ulceration, and higher mitotic rate are correlated with regional nodal metastasis. In addition, lymphovascular invasion, epithelioid cell type, and microsatellitosis are correlated with melanoma-related death. PMID:23818735

  6. [Role of HIF-induced EMT in invasion and
metastasis of tumor].

    PubMed

    Chen, Yang; Shi, Yan; Dai, Guanghai

    2016-08-01

    Hypoxia plays a vital role in tumor metabolism, proliferation, apoptosis, invasion and metastasis via hypoxia-inducible factor (HIF). Epithelial to mesenchymal transition (EMT) is a crucial process to metastasis, which could be triggered by hypoxia. EMT could be regulated by HIF via multiple pathways including TGF-β, Notch, and Wnt/β-catenin. It has been shown that anti-HIF drugs combined with anti-EMT therapies could be a promising strategy for tumor therapy. PMID:27600018

  7. Anti-CCL2: building a reservoir or opening the floodgates to metastasis?

    PubMed

    Hitchcock, Jessica R; Watson, Christine J

    2015-05-21

    Neutralisation of macrophage chemoattractant C-C chemokine ligand 2 (CCL2) has shown reduced metastasis and enhanced survival in numerous experimental models of tumorigenesis. However, important new findings reported in Nature by Momo Bentires-Alj's laboratory demonstrate that withdrawal of anti-CCL2 treatment accelerates lung metastasis and death in mice. The study highlights the need to consider longer term consequences of therapeutic intervention of metastatic disease, especially with regard to transient interference with the tumour microenvironment.

  8. Distant metastasis from oral cancer: A review and molecular biologic aspects.

    PubMed

    Irani, Soussan

    2016-01-01

    Oral squamous cell carcinoma (OSCC) has been estimated to be the sixth most common cancer worldwide. The distant metastasis plays a critical role in the management and prognosis in oral cancer patients. Regarding the distant metastasis from the oral cancer, the hypopharynx is the most common primary site, followed by the base of tongue and anterior tongue. The present review article analyzes the characteristics of the distant metastases from the oral cavity from 1937 to 2015. PMID:27583211

  9. Breast metastasis from recurrent gallbladder adenocarcinoma: a case report with review of the literature

    PubMed Central

    Faouzi, Houssin; Salmi, Nariman; Ettahri, Hamza; Elghissassi, Ibrahim; Mrabti, Hind; Errihani, Hassan

    2016-01-01

    Gallbladder adenocarcinoma has a poor prognostic. The leading modes of dissemination in gallbladder cancer (GBC) are lymphatic, vascular, neural, intraperitoneal, and intraductal. The most common site of dissemination is liver. Breast metastasis in GBC is an unusual site of dissemination. Only few cases have been reported in the literature. We report a rare case of solitary breast metastasis from recurrent gallbladder carcinoma in light of existing literature. PMID:27512606

  10. [A single metastasis in the carpal bones as the first clinical manifestation of a hepatocellular carcinoma].

    PubMed

    Corrales Pinzón, R; Alonso Sánchez, J M; de la Mano González, S; El Karzazi Tarazona, K

    2014-01-01

    Hepatocellular carcinoma is the most common primary tumor of the liver. Spreading outside the liver usually takes place in advanced stages of the disease, and bone is the third most common site of metastases. We present a case of hepatocellular carcinoma in which the first clinical manifestation was a single metastasis to the carpal bones. The interest of this case lies in the way this hepatocellular carcinoma manifested as well as in the unusual site of the metastasis.

  11. Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer.

    PubMed

    Wu, Kerui; Fukuda, Koji; Xing, Fei; Zhang, Yingyu; Sharma, Sambad; Liu, Yin; Chan, Michael D; Zhou, Xiaobo; Qasem, Shadi A; Pochampally, Radhika; Mo, Yin-Yuan; Watabe, Kounosuke

    2015-04-10

    Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis.

  12. Distant metastasis from oral cancer: A review and molecular biologic aspects

    PubMed Central

    Irani, Soussan

    2016-01-01

    Oral squamous cell carcinoma (OSCC) has been estimated to be the sixth most common cancer worldwide. The distant metastasis plays a critical role in the management and prognosis in oral cancer patients. Regarding the distant metastasis from the oral cancer, the hypopharynx is the most common primary site, followed by the base of tongue and anterior tongue. The present review article analyzes the characteristics of the distant metastases from the oral cavity from 1937 to 2015. PMID:27583211

  13. Cutaneous metastasis: a rare herald of a silent cancer.

    PubMed

    Hussain, Jonathan; Westerveld, Donevan; Sattari, Maryam

    2016-01-01

    A 59-year-old previously healthy man with a 50-pack-year smoking history presented with rib pain 1 month after a mechanical fall. Physical examination revealed a 1.5 cm right cervical lymph node and a 0.9 × 0.9 cm scalp nodule. The patient had only noticed the scalp lesion a month prior to presentation. Chest X-ray revealed a 5.8 × 5.0 cm left infrahilar mass. CT angiography demonstrated extensive metastatic mediastinal and right hilar adenopathy as well as hepatic, right adrenal and brain lesions. Pathology from fine-needle aspiration of cervical lymph nodes and punch biopsy of the scalp lesion were consistent with non-small cell lung cancer (NSCLC) metastasis. The patient underwent brain stereotactic radiosurgery and palliative radiation therapy. Unfortunately, he passed away 4 months after diagnosis. Malignancy (primary or secondary) should be considered by clinicians in the work up of patients with new skin lesions, particularly in those at high risk of cancer. PMID:26783009

  14. Local nano-mechanical properties in cancer metastasis

    NASA Astrophysics Data System (ADS)

    Bastatas, Lyndon; Martinez-Zaguilan, Raul; Sennoune, Souad; Park, Soyeun

    2011-03-01

    We investigated whether the local nano-mechanical properties of cells can represent metastatic potential using the Atomic Force Microscope. As models, we used the lowly (LNCaP) and highly (CL1) metastatic prostate cancer cells. By varying the applied forces, we determined the heterogeneity in the local elastic properties of cells in the vertical direction. We also obtained the 2D array of the force-distance curves over the entire region of cells to investigate the lateral heterogeneity of local elastic moduli. By analyzing the force-distance curves using the Hertz and the advanced models, we delineated the 2D maps of elastic moduli and adhesiveness of cells. We found that the CL1 is more heterogeneous in the local elastic moduli compared to LNCaP. We also found that the CL1 adheres much better on the substrates than the LNCaP. The enhanced adhesion generates the tensional force and thus results in higher elastic moduli. We conclude that there is an optimal range of elastic moduli to make cells actively elicit the directional movements, leading to the enhance metastasis. We will discuss our results correlated with our intercellular calcium transit.

  15. Patterns of metastasis in colon and rectal cancer

    PubMed Central

    Riihimäki, Matias; Hemminki, Akseli; Sundquist, Jan; Hemminki, Kari

    2016-01-01

    Investigating epidemiology of metastatic colon and rectal cancer is challenging, because cancer registries seldom record metastatic sites. We used a population based approach to assess metastatic spread in colon and rectal cancers. 49,096 patients with colorectal cancer were identified from the nationwide Swedish Cancer Registry. Metastatic sites were identified from the National Patient Register and Cause of Death Register. Rectal cancer more frequently metastasized into thoracic organs (OR = 2.4) and the nervous system (1.5) and less frequently within the peritoneum (0.3). Mucinous and signet ring adenocarcinomas more frequently metastasized within the peritoneum compared with generic adenocarcinoma (3.8 [colon]/3.2 [rectum]), and less frequently into the liver (0.5/0.6). Lung metastases occurred frequently together with nervous system metastases, whereas peritoneal metastases were often listed with ovarian and pleural metastases. Thoracic metastases are almost as common as liver metastases in rectal cancer patients with a low stage at diagnosis. In colorectal cancer patients with solitary metastases the survival differed between 5 and 19 months depending on T or N stage. Metastatic patterns differ notably between colon and rectal cancers. This knowledge should help clinicians to identify patients in need for extra surveillance and gives insight to further studies on the mechanisms of metastasis. PMID:27416752

  16. Targeting Serglycin Prevents Metastasis in Murine Mammary Carcinoma

    PubMed Central

    Roy, Ananya; Femel, Julia; Huijbers, Elisabeth J. M.; Spillmann, Dorothe; Larsson, Erik; Ringvall, Maria; Olsson, Anna-Karin; Åbrink, Magnus

    2016-01-01

    In hematopoietic cells, serglycin proteoglycans mainly contribute to proper storage and secretion of inflammatory mediators via their negatively charged glycosaminoglycans. Serglycin proteoglycans are also expressed in cancer cells where increased expression has been linked to poor prognosis. However, the serglycin-dependent mediators promoting cancer progression remain to be determined. In the present study we report that genetic ablation of serglycin proteoglycan completely blocks lung metastasis in the MMTV-PyMT-driven mouse breast cancer model, while serglycin-deficiency did not affect primary tumour growth or number of mammary tumours. Although E-cadherin expression was higher in the serglycin-deficient primary tumour tissue, indicating reduced invasiveness, serglycin-deficient tumour cells were still detected in the circulation. These data suggest that serglycin proteoglycans play a role in extravasation as well as colonization and growth of metastatic cells. A microarray expression analysis and functional annotation of differentially expressed genes identified several biological pathways where serglycin may be important. Our results suggest that serglycin and serglycin-dependent mediators are potential drug targets to prevent metastatic disease/dissemination of cancer. PMID:27223472

  17. Predictors of limph node metastasis in endometrial cancer

    PubMed Central

    IGNAT, FLORIN LAURENTIU; IRIMIE, ALEXANDRU; COSTIN, NICOLAE; ACHIMAS-CADARIU, PATRICIU; LISENCU, IOAN COSMIN

    2013-01-01

    Introduction Endometrial cancer is the most common gynecologic malignancy in developed countries. The adequate surgical staging proposed by FIGO (International Federation for Gynaecology and Obstetrics) advocates lymphadenectomy; however, it does not establish the indications, the type and the extent of lymphadenectomy, thus generating multiple controversies. Methods Retrospective, analytical study of patients treated surgically for endometrial adenocarcinoma in the Oncological Institute ”Prof. Dr. Ion Chiricuţă” Cluj-Napoca (IOCN) between January 2008 and December 2012 – 709 cases eligible for the study. Results 206 pelvic and/or paraaortic lymphadenectomies were performed, the average number of excised lymph nodes being 15.6. Overall in 4.4% of patients the lymph nodes were affected by metastases. The presence of each risk factor analysed was statistically significantly associated with lymph node metastasis (p<0.05). Age above 55 years was statistically significantly associated (p<0.05) with the presence of negative prognostic factors in the study. Conclusions The analysed histopathological and clinical prognostic factors were statistically significantly associated with lymphatic dissemination in endometrial cancer. We recommend treating endometrial cancer in tertiary centres by surgeons or gynaecologists-oncologists with experience in extensive peritoneal and retroperitoneal surgery. PMID:26527979

  18. Spontaneous Rupture of Hepatic Metastasis from Pancreatic Adenocarcinoma.

    PubMed

    Rahul, Anil; Robin, Fernandes; Adarsh, Hiremath

    2016-01-01

    A 58-year-old man with advanced-stage pancreatic adenocarcinoma presented with fatigue and dyspnea. Examination revealed tachycardia (102 b/min) with mild tenderness in right upper quadrant. His hemoglobin (Hb) was 7.9 g/dL (10 days prior to presentation 12.2 g/dL), International normalized ratio (INR), platelet count was normal, and the stool guaiac test was negative. On admission, abdominal computed tomography (CT) scan showed hepatic metastatic lesion with a rupture and hemoperitoneum communicating to the subdiaphragmatic space. This rapid progression of anemia along with presenting symptoms and CT imaging were attributed to diagnosis of spontaneous rupture of liver metastasis from pancreatic adenocarcinoma. Patient received blood transfusion and hemoglobin was monitored in successive intervals. His general condition and anemia improved with conservative management and he was discharged in 3 days. Repeated CT after 4 months showed resolving hemoperitoneum and stable hemoglobin levels. The patient deceased 9 months after being diagnosed. A literature search revealed limited data regarding the incidence and management of spontaneous rupture of metastatic lesion secondary to pancreatic adenocarcinoma which has been managed conservatively and thus we are reporting our experience. PMID:27597912

  19. PHOX2B is a suppressor of neuroblastoma metastasis

    PubMed Central

    Naftali, Osnat; Maman, Shelly; Meshel, Tsipi; Sagi-Assif, Orit; Ginat, Ravit; Witz, Isaac P.

    2016-01-01

    Paired like homeobox 2B (PHOX2B) is a minimal residual disease (MRD) marker of neuroblastoma. The presence of MRD, also referred to as micro-metastases, is a powerful marker of poor prognosis in neuroblastoma. Lung metastasis is considered a terminal event in neuroblastoma. Lung micro-metastatic neuroblastoma (MicroNB) cells show high expression levels of PHOX2B and possess a less malignant and metastatic phenotype than lung macro metastatic neuroblastoma (MacroNB) cells, which hardly express PHOX2B. In vitro assays showed that PHOX2B knockdown in MicroNB cells did not affect cell viability; however it decreased the migratory capacity of the MicroNB-shPHOX2B cells. An orthotopic inoculation of MicroNB-shPHOX2B cells into the adrenal gland of nude mice resulted in significantly larger primary tumors and a heavier micro-metastatic load in the lungs and bone-marrow, than when control cells were inoculated. PHOX2B expression was found to be regulated by methylation. The PHOX2B promoter in MacroNB cells is significantly more methylated than in MicroNB cells. Demethylation assays using 5-azacytidine demonstrated that methylation can indeed inhibit PHOX2B transcription in MacroNB cells. These pre-clinical data strongly suggest that PHOX2B functions as a suppressor of neuroblastoma progression. PMID:26840262

  20. STAT3 regulated ARF expression suppresses prostate cancer metastasis

    PubMed Central

    Pencik, Jan; Schlederer, Michaela; Gruber, Wolfgang; Unger, Christine; Walker, Steven M.; Chalaris, Athena; Marié, Isabelle J.; Hassler, Melanie R.; Javaheri, Tahereh; Aksoy, Osman; Blayney, Jaine K.; Prutsch, Nicole; Skucha, Anna; Herac, Merima; Krämer, Oliver H.; Mazal, Peter; Grebien, Florian; Egger, Gerda; Poli, Valeria; Mikulits, Wolfgang; Eferl, Robert; Esterbauer, Harald; Kennedy, Richard; Fend, Falko; Scharpf, Marcus; Braun, Martin; Perner, Sven; Levy, David E.; Malcolm, Tim; Turner, Suzanne D.; Haitel, Andrea; Susani, Martin; Moazzami, Ali; Rose-John, Stefan; Aberger, Fritz; Merkel, Olaf; Moriggl, Richard; Culig, Zoran; Dolznig, Helmut; Kenner, Lukas

    2015-01-01

    Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition. PMID:26198641

  1. Pattern Recognition Receptors in Cancer Progression and Metastasis

    PubMed Central

    Pandey, Sanjay; Singh, Saurabh; Anang, Vandana; Bhatt, Anant N; Natarajan, K; Dwarakanath, Bilikere S

    2015-01-01

    The innate immune system is an integral component of the inflammatory response to pathophysiological stimuli. Toll-like receptors (TLRs) and inflammasomes are the major sensors and pattern recognition receptors (PRRs) of the innate immune system that activate stimulus (signal)-specific pro-inflammatory responses. Chronic activation of PRRs has been found to be associated with the aggressiveness of various cancers and poor prognosis. Involvement of PRRs was earlier considered to be limited to infection- and injury-driven carcinogenesis, where they are activated by pathogenic ligands. With the recognition of damage-associated molecular patterns (DAMPs) as ligands of PRRs, the role of PRRs in carcinogenesis has also been implicated in other non-pathogen-driven neoplasms. Dying (apoptotic or necrotic) cells shed a plethora of DAMPs causing persistent activation of PRRs, leading to chronic inflammation and carcinogenesis. Such chronic activation of TLRs promotes tumor cell proliferation and enhances tumor cell invasion and metastasis by regulating pro-inflammatory cytokines, metalloproteinases, and integrins. Due to the decisive role of PRRs in carcinogenesis, targeting PRRs appears to be an effective cancer-preventive strategy. This review provides a brief account on the association of PRRs with various cancers and their role in carcinogenesis. PMID:26279628

  2. Physical biology in cancer. 1. Cellular physics of cancer metastasis.

    PubMed

    Moore, Nicole M; Nagahara, Larry A

    2014-01-15

    One of the major challenges in cancer research today is developing new therapeutic strategies to control metastatic disease, the spread of cancer cells from a primary tumor to seed in a distant site. Advances in diagnosis and treatment options have increased the survival rate for most patients with local tumors; however, less progress has been made in treatment of disseminated disease. According to the SEER Cancer Statistics Review, 1975-2010, in the case of breast and prostate cancers, only one in four patients diagnosed with distant metastatic disease will survive more than five years. Current research efforts largely focus on identifying biological targets, such as specific genes and signaling pathways that drive two key steps of metastasis, invasion from the primary tumor and growth in the secondary site. On the other hand, there are phenotypic traits and dynamics in the metastatic process that are not encoded by single genes or signaling pathways but, rather, a larger system of events and biophysical characteristics. Connecting genomic and pathway investigations with quantitative physical phenotypic characteristics of cells, the physical microenvironment, and the physical spatiotemporal interactions of the metastatic process provides a stronger complementary understanding of the disease.

  3. Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis.

    PubMed

    Lehuédé, Camille; Dupuy, Fanny; Rabinovitch, Rebecca; Jones, Russell G; Siegel, Peter M

    2016-09-15

    Cancer cells must adapt their metabolism to meet the energetic and biosynthetic demands that accompany rapid growth of the primary tumor and colonization of distinct metastatic sites. Different stages of the metastatic cascade can also present distinct metabolic challenges to disseminating cancer cells. However, little is known regarding how changes in cellular metabolism, both within the cancer cell and the metastatic microenvironment, alter the ability of tumor cells to colonize and grow in distinct secondary sites. This review examines the concept of metabolic heterogeneity within the primary tumor, and how cancer cells are metabolically coupled with other cancer cells that comprise the tumor and cells within the tumor stroma. We examine how metabolic strategies, which are engaged by cancer cells in the primary site, change during the metastatic process. Finally, we discuss the metabolic adaptations that occur as cancer cells colonize foreign metastatic microenvironments and how cancer cells influence the metabolism of stromal cells at sites of metastasis. Through a discussion of these topics, it is clear that plasticity in tumor metabolic programs, which allows cancer cells to adapt and grow in hostile microenvironments, is emerging as an important variable that may change clinical approaches to managing metastatic disease. Cancer Res; 76(18); 5201-8. ©2016 AACR. PMID:27587539

  4. Brain Metastasis-Initiating Cells: Survival of the Fittest

    PubMed Central

    Singh, Mohini; Manoranjan, Branavan; Mahendram, Sujeivan; McFarlane, Nicole; Venugopal, Chitra; Singh, Sheila K.

    2014-01-01

    Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only months. Despite the high rate of BM-associated mortality, very little research is conducted in this area. Lack of research and staggeringly low patient survival is indicative that a novel approach to BMs and their treatment is needed. The ability of a small subset of primary tumor cells to produce macrometastases is reminiscent of brain tumor-initiating cells (BTICs) or cancer stem cells (CSCs) hypothesized to form primary brain tumors. BTICs are considered stem cell-like due to their self-renewal and differentiation properties. Similar to the subset of cells forming metastases, BTICs are most often a rare subpopulation. Based on the functional definition of a TIC, cells capable of forming a BM could be considered to be brain metastasis-initiating cells (BMICs). These putative BMICs would not only have the ability to initiate tumor growth in a secondary niche, but also the machinery to escape the primary tumor, migrate through the circulation, and invade the neural niche. PMID:24857921

  5. Motif mimetic of epsin perturbs tumor growth and metastasis

    PubMed Central

    Dong, Yunzhou; Wu, Hao; Rahman, H.N. Ashiqur; Liu, Yanjun; Pasula, Satish; Tessneer, Kandice L.; Cai, Xiaofeng; Liu, Xiaolei; Chang, Baojun; McManus, John; Hahn, Scott; Dong, Jiali; Brophy, Megan L.; Yu, Lili; Song, Kai; Silasi-Mansat, Robert; Saunders, Debra; Njoku, Charity; Song, Hoogeun; Mehta-D’Souza, Padmaja; Towner, Rheal; Lupu, Florea; McEver, Rodger P.; Xia, Lijun; Boerboom, Derek; Srinivasan, R. Sathish; Chen, Hong

    2015-01-01

    Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium–targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin–interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium–specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy. PMID:26571402

  6. Therapeutic options for peritoneal metastasis arising from colorectal cancer

    PubMed Central

    Glockzin, Gabriel; Schlitt, Hans J; Piso, Pompiliu

    2016-01-01

    Peritoneal metastasis is a common sign of advanced tumor stage, tumor progression or tumor recurrence in patients with colorectal cancer. Due to the improvement of systemic chemotherapy, the development of targeted therapy and the introduction of additive treatment options such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), the therapeutic approach to peritoneal metastatic colorectal cancer (pmCRC) has changed over recent decades, and patient survival has improved. Moreover, in contrast to palliative systemic chemotherapy or best supportive care, the inclusion of CRS and HIPEC as inherent components of a multidisciplinary treatment regimen provides a therapeutic approach with curative intent. Although CRS and HIPEC are increasingly accepted as the standard of care for selected patients and have become part of numerous national and international guidelines, the individual role, optimal timing and ideal sequence of the different systemic, local and surgical treatment options remains a matter of debate. Ongoing and future randomized controlled clinical trials may help clarify the impact of the different components, allow for further improvement of patient selection and support the standardization of oncologic treatment regimens for pmCRC. The addition of further therapeutic options such as neoadjuvant intraperitoneal chemotherapy or pressurized intraperitoneal aerosol chemotherapy, should be investigated to optimize therapeutic regimens and further improve the oncological outcome.

  7. Mucoepidermoid carcinoma of the conjunctiva with lung metastasis.

    PubMed

    Rishi, Pukhraj; Sharma, Rashi; Subramanian, Krishnakumar; Subramaniam, Nirmala

    2015-05-01

    A 36-year-old lady presented with redness and decreased vision in right eye since 6 months. She was earlier diagnosed of cavitary lung lesion, presumed secondary to tuberculosis and treated with anti-tubercular treatment for 4 months. Examination of affected right eye revealed nil light perception, conjunctival congestion with an exuberant mass in the inferotemporal bulbar conjunctiva, proptosis, iris neovascularization, 360° closed angles, intraocular pressure of 48 mm Hg, exudative retinal detachment, uveal mass and orbital extension. A diagnostic needle biopsy of uveal mass revealed malignant cells. Computed tomography-guided lung biopsy revealed squamous cell carcinoma (SCC), indicating metastatic spread from the orbit. She underwent lid-sparing exenteration of the right eye. Histopathological examination of the orbital tissue revealed mucoepidermoid carcinoma arising from the conjunctiva with extensive invasion into the orbital tissue, muscle fibers, sclera, choroid and optic nerve. Multiple tumor emboli were seen in the lumen of orbital blood vessels. In conclusion, mucoepidermoid carcinoma of the conjunctiva is a rare, aggressive variant of SCC. Early intervention is essential to prevent intraocular invasion and systemic metastasis. PMID:26139812

  8. Microfluidic Device for Studying Tumor Cell Extravasation in Cancer Metastasis

    SciTech Connect

    Lin, Henry K; Thundat, Thomas George; Evans III, Boyd Mccutchen; Datar, Ram H; Reese, Benjamin E; Zheng, Siyang

    2010-01-01

    Metastasis is the process by which cancer spreads to form secondary tumors at downstream locations throughout the body. This uncontrolled spreading is the leading cause of death in patients with epithelial cancers and is the main reason that suppressing and targeting cancer has proven to be so challenging. Tumor cell extravasation is one of the key steps in cancer s progression towards a metastatic state. This occurs when circulating tumor cells found within the blood stream are able to transmigrate through the endothelium lining and basement membrane of the vasculature to form metastatic tumors at secondary sites within the body. Predicting the likelihood of this occurrence in patients, or being able to determine specific markers involved in this process could lead to preventative measures targeting these types of cancer; moreover, this may lead to the discovery of novel anti-metastatic drugs. We have developed a microfluidic device that has shown the extravasation of fluorescently labeled tumor cells across an endothelial cell lined membrane coated with matrigel followed by the formation of colonies. This device provides the advantages of combining a controlled environment, mimicking that found within the body, with real-time monitoring capabilities allowing for the study of these biomarkers and cellular interactions along with other potential mechanisms involved in the process of extravasation.

  9. Pulmonary metastasis after bleomycin-induced endothelial injury and repair

    SciTech Connect

    Adamson, I.Y.R.; Young, L.; Orr, F.W.

    1986-03-01

    Injury to the endothelial barrier is thought to enhance the localization and metastasis of circulating tumor cells. This hypothesis was tested by inducing pulmonary endothelial injury in C57bl/6 mice by injecting a single IV dose of bleomycine (120 mg/kg). After 5 days, severe endothelial injury was demonstrated by morphology and by increased levels of protein in lung lavage fluid. When /sup 131/I-iododeoxyuridine labeled syngeneic fibrosarcoma cells were injected IV at this time, a 9 fold increase in their localization was detected 24 hrs later in bleomycin-treated lungs compared to saline controls. By EM, tumor cells were observed at sites of denuded vascular basement membrane. There was also a significant increase in subsequent gross metastases and percentage of lung occupied by tumor in the bleomycin group. Animals examined 10 days after bleomycin showed less endothelial damage and a smaller increase in tumor cell localization and metastases. At 21 days, when endothelial structure and alveolar protein levels had returned to normal, and at 6 weeks, when there was focal fibrosis, no increase in tumor cell localization or metastases was found. It is concluded that damage to the pulmonary endothelium is a key factor in enhancing the trapping of circulating tumor cells and increasing metastatic tumor growth.

  10. Brain metastasis-initiating cells: survival of the fittest.

    PubMed

    Singh, Mohini; Manoranjan, Branavan; Mahendram, Sujeivan; McFarlane, Nicole; Venugopal, Chitra; Singh, Sheila K

    2014-05-22

    Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only months. Despite the high rate of BM-associated mortality, very little research is conducted in this area. Lack of research and staggeringly low patient survival is indicative that a novel approach to BMs and their treatment is needed. The ability of a small subset of primary tumor cells to produce macrometastases is reminiscent of brain tumor-initiating cells (BTICs) or cancer stem cells (CSCs) hypothesized to form primary brain tumors. BTICs are considered stem cell-like due to their self-renewal and differentiation properties. Similar to the subset of cells forming metastases, BTICs are most often a rare subpopulation. Based on the functional definition of a TIC, cells capable of forming a BM could be considered to be brain metastasis-initiating cells (BMICs). These putative BMICs would not only have the ability to initiate tumor growth in a secondary niche, but also the machinery to escape the primary tumor, migrate through the circulation, and invade the neural niche.

  11. Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis.

    PubMed

    Lehuédé, Camille; Dupuy, Fanny; Rabinovitch, Rebecca; Jones, Russell G; Siegel, Peter M

    2016-09-15

    Cancer cells must adapt their metabolism to meet the energetic and biosynthetic demands that accompany rapid growth of the primary tumor and colonization of distinct metastatic sites. Different stages of the metastatic cascade can also present distinct metabolic challenges to disseminating cancer cells. However, little is known regarding how changes in cellular metabolism, both within the cancer cell and the metastatic microenvironment, alter the ability of tumor cells to colonize and grow in distinct secondary sites. This review examines the concept of metabolic heterogeneity within the primary tumor, and how cancer cells are metabolically coupled with other cancer cells that comprise the tumor and cells within the tumor stroma. We examine how metabolic strategies, which are engaged by cancer cells in the primary site, change during the metastatic process. Finally, we discuss the metabolic adaptations that occur as cancer cells colonize foreign metastatic microenvironments and how cancer cells influence the metabolism of stromal cells at sites of metastasis. Through a discussion of these topics, it is clear that plasticity in tumor metabolic programs, which allows cancer cells to adapt and grow in hostile microenvironments, is emerging as an important variable that may change clinical approaches to managing metastatic disease. Cancer Res; 76(18); 5201-8. ©2016 AACR.

  12. Inflammatory metastatic breast cancer with gallbladder metastasis: an incidental finding.

    PubMed

    Ebrahim, Hassan; Graham, David; Rice, David; Ribadeneyra, Michael; Thorner, Kim; Shipley, William; Wehmueller, Michael

    2015-07-01

    Breast cancer is the most frequently diagnosed cancer in women, with an estimated 231,840 new cases representing 14.0% of all new cancer cases in the United States in 2015. Early screening and modern techniques of imaging and diagnosis have led to a significant improvement in detecting early-stage breast cancers and to a decrease in the incidence of metastatic breast cancer (MBC). About 20%-30% of patients who are initially diagnosed with an early-stage, nonmetastatic breast cancer will subsequently develop a distant metastatic disease. Between 6%-10% of the new breast cancer cases present initially as stage IV, referred to as de novo MBC. The most common sites of breast cancer metastases are lymph nodes, chest wall, skeleton, lung, skin, and the central nervous system (CNS). Lobular carcinoma, in particular, may metastasize to the gastrointestinal tract, peritoneum, and retroperitoneum. Gallbladder metastasis from breast cancer is very rare, and only 15-20 cases have been reported in the literature. Most of those cases have been associated particularly with a lobular histology. We report an additional rare case of MBC to the gallbladder, but with a ductal histology. PMID:26270542

  13. Therapeutic options for peritoneal metastasis arising from colorectal cancer.

    PubMed

    Glockzin, Gabriel; Schlitt, Hans J; Piso, Pompiliu

    2016-08-01

    Peritoneal metastasis is a common sign of advanced tumor stage, tumor progression or tumor recurrence in patients with colorectal cancer. Due to the improvement of systemic chemotherapy, the development of targeted therapy and the introduction of additive treatment options such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), the therapeutic approach to peritoneal metastatic colorectal cancer (pmCRC) has changed over recent decades, and patient survival has improved. Moreover, in contrast to palliative systemic chemotherapy or best supportive care, the inclusion of CRS and HIPEC as inherent components of a multidisciplinary treatment regimen provides a therapeutic approach with curative intent. Although CRS and HIPEC are increasingly accepted as the standard of care for selected patients and have become part of numerous national and international guidelines, the individual role, optimal timing and ideal sequence of the different systemic, local and surgical treatment options remains a matter of debate. Ongoing and future randomized controlled clinical trials may help clarify the impact of the different components, allow for further improvement of patient selection and support the standardization of oncologic treatment regimens for pmCRC. The addition of further therapeutic options such as neoadjuvant intraperitoneal chemotherapy or pressurized intraperitoneal aerosol chemotherapy, should be investigated to optimize therapeutic regimens and further improve the oncological outcome. PMID:27602235

  14. Hepatoblastoma of the adult with pericardial metastasis: A case report

    PubMed Central

    Celotti, Andrea; Baiocchi, Gian Luca; Ceresoli, Marco; Bartoli, Michele; Ulinici, Silvia; Portolani, Nazario

    2016-01-01

    Background Hepatoblastoma is the most frequent liver tumor in children, but very rare in the adult and associated with an unfavorable prognosis. The diagnosis is always postoperative or post mortem and biopsy is not useful. Surgery is the only accepted treatment. Case presentation Our patient underwent surgery in the suspect of liver metastasis from a previous gastric cancer. Surgery consisted in left lobectomy with partial diaphragm resection and partial pericardiectomy for a pericardial lesion, found after the opening of the thorax. The diaphragm defect was corrected with a biological mesh. Results The histopathological examination indicated hepatoblastoma of the adult with pericardial metastases. The patient was asymptomatic and without recurrence after 21 months of follow up. Conclusion The hepatoblastoma of the adult is related to a poor prognosis with median survival time less than 5 months. Surgery is the only curative treatment, but in many cases tumor resection requires complex operations. Vascular and thoracic expertise could be useful in the management of hepatoblastoma. PMID:26826931

  15. Studying the Role of Alveolar Macrophages in Breast Cancer Metastasis.

    PubMed

    Vadrevu, Surya Kumari; Sharma, Sharad; Chintala, Navin; Patel, Jalpa; Karbowniczek, Magdalena; Markiewski, Maciej

    2016-01-01

    This paper describes the application of the syngeneic model of breast cancer (4T1) to the studies on a role of pulmonary alveolar macrophages in cancer metastasis. The 4T1 cells expressing GFP in combination with imaging and confocal microscopy are used to monitor tumor growth, track metastasizing tumor cells, and quantify the metastatic burden. These approaches are supplemented by digital histopathology that allows the automated and unbiased quantification of metastases. In this method the routinely prepared histological lung sections, which are stained with hematoxylin and eosin, are scanned and converted to the digital slides that are then analyzed by the self-trained pattern recognition software. In addition, we describe the flow cytometry approaches with the use of multiple cell surface markers to identify alveolar macrophages in the lungs. To determine impact of alveolar macrophages on metastases and antitumor immunity these cells are depleted with the clodronate-containing liposomes administrated intranasally to tumor-bearing mice. This approach leads to the specific and efficient depletion of this cell population as confirmed by flow cytometry. Tumor volumes and lung metastases are evaluated in mice depleted of alveolar macrophages, to determine the role of these cells in the metastatic progression of breast cancer. PMID:27403530

  16. Therapeutic options for peritoneal metastasis arising from colorectal cancer

    PubMed Central

    Glockzin, Gabriel; Schlitt, Hans J; Piso, Pompiliu

    2016-01-01

    Peritoneal metastasis is a common sign of advanced tumor stage, tumor progression or tumor recurrence in patients with colorectal cancer. Due to the improvement of systemic chemotherapy, the development of targeted therapy and the introduction of additive treatment options such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), the therapeutic approach to peritoneal metastatic colorectal cancer (pmCRC) has changed over recent decades, and patient survival has improved. Moreover, in contrast to palliative systemic chemotherapy or best supportive care, the inclusion of CRS and HIPEC as inherent components of a multidisciplinary treatment regimen provides a therapeutic approach with curative intent. Although CRS and HIPEC are increasingly accepted as the standard of care for selected patients and have become part of numerous national and international guidelines, the individual role, optimal timing and ideal sequence of the different systemic, local and surgical treatment options remains a matter of debate. Ongoing and future randomized controlled clinical trials may help clarify the impact of the different components, allow for further improvement of patient selection and support the standardization of oncologic treatment regimens for pmCRC. The addition of further therapeutic options such as neoadjuvant intraperitoneal chemotherapy or pressurized intraperitoneal aerosol chemotherapy, should be investigated to optimize therapeutic regimens and further improve the oncological outcome. PMID:27602235

  17. Bilateral Choroidal Metastasis from Non-Small Cell Lung Cancer

    PubMed Central

    Namad, Tariq; Wang, Jiang; Tilton, Annemarie; Abdel Karim, Nagla

    2014-01-01

    Breast and lung cancers are the most common primary neoplasms to manifest with choroidal metastases. The incidence of choroidal metastases from metastatic lung cancer was reported to be 2–6.7%. We report a case of bilateral choroidal metastasis from non-small cell lung cancer. A 59-year-old Caucasian female patient, never a smoker, was diagnosed with stage IV lung adenocarcinoma metastatic to the pleura, bones, and the brain. Her initial scan of the chest showed innumerable soft tissue nodules and mediastinal adenopathy compatible with metastatic disease. Her initial brain MRI showed numerous small enhancing lesions consistent with extensive disease. Unfortunately, during her follow-up visits, she presented with bulge on her left eye. Simultaneously, her follow-up chest scan showed increase in the size of the lung nodules. She continued to have a reasonable performance status at that time, except for mild increase in her dyspnea. The choroidal metastases require a multidisciplinary care and should be among the differential patients with malignancy who present with ocular symptoms. PMID:25295203

  18. Infrequent Loss of Luminal Differentiation in Ductal Breast Cancer Metastasis

    PubMed Central

    Calvo, Julia; Sánchez-Cid, Lourdes; Muñoz, Montserrat; Lozano, Juan José; Thomson, Timothy M.; Fernández, Pedro L.

    2013-01-01

    Lymph node involvement is a major prognostic variable in breast cancer. Whether the molecular mechanisms that drive breast cancer cells to colonize lymph nodes are shared with their capacity to form distant metastases is yet to be established. In a transcriptomic survey aimed at identifying molecular factors associated with lymph node involvement of ductal breast cancer, we found that luminal differentiation, assessed by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) and GATA3, was only infrequently lost in node-positive primary tumors and in matched lymph node metastases. The transcription factor GATA3 critically determines luminal lineage specification of mammary epithelium and is widely considered a tumor and metastasis suppressor in breast cancer. Strong expression of GATA3 and ER in a majority of primary node-positive ductal breast cancer was corroborated by quantitative RT-PCR and immunohistochemistry in the initial sample set, and by immunohistochemistry in an additional set from 167 patients diagnosed of node-negative and –positive primary infiltrating ductal breast cancer, including 102 samples from loco-regional lymph node metastases matched to their primary tumors, as well as 37 distant metastases. These observations suggest that loss of luminal differentiation is not a major factor driving the ability of breast cancer cells to colonize regional lymph nodes. PMID:24205108

  19. Exosomes in development, metastasis and drug resistance of breast cancer.

    PubMed

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-08-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. PMID:26052865

  20. Tpl2 induces castration resistant prostate cancer progression and metastasis.

    PubMed

    Lee, Hye Won; Cho, Hyun Jung; Lee, Se Jeong; Song, Hye Jin; Cho, Hee Jin; Park, Min Chul; Seol, Ho Jun; Lee, Jung-Il; Kim, Sunghoon; Lee, Hyun Moo; Choi, Han Yong; Nam, Do-Hyun; Joo, Kyeung Min

    2015-05-01

    Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC. PMID:25274482

  1. Pancreatic metastasis from mycosis fungoides mimicking primary pancreatic tumor

    PubMed Central

    Ceriolo, Paola; Fausti, Valentina; Cinotti, Elisa; Bonadio, Silvia; Raffaghello, Lizzia; Bianchi, Giovanna; Orcioni, Giulio Fraternali; Fiocca, Roberto; Rongioletti, Franco; Pistoia, Vito; Borgonovo, Giacomo

    2016-01-01

    Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that can undergo local progression with possible systemic dissemination. We report a case of a patient affected by MF with a pancreatic mass that was a diagnostic challenge between primitive tumor and pancreatic metastasis from MF. Clinical setting findings and imaging studies raised the suspicion of a pancreatic primary neoplasm. A diagnostic clue was provided by the combined histomorphologic/immunohistochemical study of pancreatic and cutaneous biopsies, which revealed a pancreatic localization of MF. Considering the rarity of metastatic localization of MF to the pancreas, we next investigated whether chemokine-chemokine receptor interactions could be involved in the phenomenon to provide new insight into the possible mechanisms underlying metastatic localization of MF to the pancreas. Histological analyses of archival pancreatic tissue demonstrated that glucagon-secreting cells of the pancreatic islets expressed the CCL27 chemokine, which may have attracted in our case metastatic MF cells expressing the complementary receptor CCR10. PMID:27022231

  2. Exosomes in development, metastasis and drug resistance of breast cancer.

    PubMed

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-08-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system.

  3. Dynamics of tissue topology during cancer invasion and metastasis

    NASA Astrophysics Data System (ADS)

    Munn, Lance L.

    2013-12-01

    During tumor progression, cancer cells mix with other cell populations including epithelial and endothelial cells. Although potentially important clinically as well as for our understanding of basic tumor biology, the process of mixing is largely a mystery. Furthermore, there is no rigorous, analytical measure available for quantifying the mixing of compartments within a tumor. I present here a mathematical model of tissue repair and tumor growth based on collective cell migration that simulates a wide range of observed tumor behaviors with correct tissue compartmentalization and connectivity. The resulting dynamics are analyzed in light of the Euler characteristic number (χ), which describes key topological features such as fragmentation, looping and cavities. The analysis predicts a number of regimes in which the cancer cells can encapsulate normal tissue, form a co-interdigitating mass, or become fragmented and encapsulated by endothelial or epithelial structures. Key processes that affect the topological changes are the production of provisional matrix in the tumor, and the migration of endothelial or epithelial cells on this matrix. Furthermore, the simulations predict that topological changes during tumor invasion into blood vessels may contribute to metastasis. The topological analysis outlined here could be useful for tumor diagnosis or monitoring response to therapy and would only require high resolution, 3D image data to resolve and track the various cell compartments.

  4. Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis.

    PubMed

    Chiodoni, Claudia; Colombo, Mario P; Sangaletti, Sabina

    2010-06-01

    The family of matricellular proteins comprises molecules with disparate biology. The main characteristic of matricellular proteins is to be expressed during tissue renewal and repair in order to "normalize" the tissue. Tumors are wound that do not heal, and tumor growth and metastasis can be viewed as a consequence of aberrant homeostasis, during which matricellular proteins are often upregulated. In the tumor microenvironment, they can be produced by both tumor cells and surrounding stromal cells, such as fibroblasts and macrophages. In this context, matricellular proteins can exert several functions that actively contribute to tumor progression. They may (a) regulate cellular adhesion and migration and extracellular matrix deposition, (b) control tumor infiltration by macrophages or other leukocytes, (c) affect tumor angiogenesis, (d) regulate TGFbeta and other growth factor receptor signals, (e) directly stimulate integrin receptors to transduce pro-survival or pro-migratory signals, and (f) regulate the wnt/beta-catenin pathways. Most of these functions contribute to settle a chronic low inflammatory state, whose involvement in tissue transformation and tumor progression is now established.

  5. Spontaneous Rupture of Hepatic Metastasis from Pancreatic Adenocarcinoma

    PubMed Central

    Robin, Fernandes; Adarsh, Hiremath

    2016-01-01

    A 58-year-old man with advanced-stage pancreatic adenocarcinoma presented with fatigue and dyspnea. Examination revealed tachycardia (102 b/min) with mild tenderness in right upper quadrant. His hemoglobin (Hb) was 7.9 g/dL (10 days prior to presentation 12.2 g/dL), International normalized ratio (INR), platelet count was normal, and the stool guaiac test was negative. On admission, abdominal computed tomography (CT) scan showed hepatic metastatic lesion with a rupture and hemoperitoneum communicating to the subdiaphragmatic space. This rapid progression of anemia along with presenting symptoms and CT imaging were attributed to diagnosis of spontaneous rupture of liver metastasis from pancreatic adenocarcinoma. Patient received blood transfusion and hemoglobin was monitored in successive intervals. His general condition and anemia improved with conservative management and he was discharged in 3 days. Repeated CT after 4 months showed resolving hemoperitoneum and stable hemoglobin levels. The patient deceased 9 months after being diagnosed. A literature search revealed limited data regarding the incidence and management of spontaneous rupture of metastatic lesion secondary to pancreatic adenocarcinoma which has been managed conservatively and thus we are reporting our experience. PMID:27597912

  6. Exosomes in development, metastasis and drug resistance of breast cancer

    PubMed Central

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-01-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. PMID:26052865

  7. Rare Presentation of Gastroesophageal Carcinoma with Rectal Metastasis: A Case Report

    PubMed Central

    Makker, Jasbir; Karki, Niraj; Sapkota, Binita; Niazi, Masooma; Remy, Prospere

    2016-01-01

    Patient: Female, 60 Final Diagnosis: Gastroesophageal carcinoma with rectal metastasis Symptoms: Bloating • constipation • weight loss Medication: — Clinical Procedure: Endoscopy • flexible sigmoidoscopy • lower endoscopic ultrasound Specialty: Gastroenterology and Hepatology Objective: Unusual clinical course Background: Gastroesophageal cancers, previously considered rare, are rapidly increasing worldwide. We present here a unique case of gastroesophageal carcinoma with metastasis to the rectum. Case Report: A 60-year-old female patient presented with constipation, bloating, and weight loss of 4-month duration. She had undergone sleeve gastrectomy 6 years before. Endoscopies performed revealed a friable-looking mucosa in the lower esophagus and a polypoid rectal mass. Histopathological examination from both the esophageal and rectal lesions revealed poorly differentiated adenocarcinoma cells. Immunohistochemistry stain from both specimens was positive for CK7 supporting the gastric site primary with metastasis to the rectum. Further evaluation also revealed metastasis to bone and malignant pleural effusion. Chemotherapy with palliative intent was initiated. Conclusions: Colorectal metastasis is commonly seen from cancers of the breast, stomach, melanoma, kidney, prostate, and ovaries. However, colorectal metastasis from gastroesophageal cancer has never been reported in the medical literature. Diagnosis relies on histopathologic examination and immunohistochemical staining of the tumor. Treatment depends on the tumor stage. Tumors with widespread metastatic disease are candidates for palliative chemotherapy. PMID:27558656

  8. shRNA-mediated knockdown of Bmi-1 inhibit lung adenocarcinoma cell migration and metastasis.

    PubMed

    Meng, Xiuxiang; Wang, Yifang; Zheng, Xiangyu; Liu, Chunqing; Su, Benli; Nie, Huiling; Zhao, Baoxia; Zhao, Xinyu; Yang, Hong

    2012-07-01

    Bmi-1 has been implicated in cancer cell growth and metastasis in a variety of tumor types. In this study, we sought to evaluate the expression of Bmi-1 in lung adenocarcinoma samples, and to determine if a correlation exists between Bmi-1 expression and clinical features of lung cancer, such as metastasis. Our results showed that Bmi-1 expression is increased in lung cancer tissues compared to adjacent non-cancerous tissues, and is associated with clinical features of lung cancer, including clinical stage and distant metastasis. We were then interested in determining if shRNA-mediated knockdown of Bmi-1 would inhibit metastasis of lung adenocarcinoma cells. To this end, we chose the most efficient shRNA duplexes targeting Bmi-1, and constructed two stably transfected lung adenocarcinoma cell lines (A549 and SPCA1). The shRNA-mediated knockdown of Bmi-1 significantly reduced migration in vitro, and metastasis in vivo, of A549 and SPCA1 cells. More importantly, knockdown of Bmi-1 also upregulated PTEN expression, and downregulated p-Akt and VEGF expression. These data support the hypothesis that Bmi-1 regulates key pathways involved in the metastasis of lung adenocarcinoma cells.

  9. Experimental melanoma metastasis in lungs of mice with congenital coagulation disorders

    PubMed Central

    Brüggemann, Lois W; Versteeg, Henri H; Niers, Tatjana M; Reitsma, Pieter H; Spek, C Arnold

    2008-01-01

    Experimental animal studies as well as clinical trials have shown that interventions targeting the blood coagulation cascade inhibit cancer cell metastasis. These data support the hypothesis that congenital prothrombotic disorders, like factor V Leiden, facilitate metastasis whereas bleeding disorders, like haemophilia impede metastasis. To test this hypothesis, we subjected factor V Leiden and factor VIII deficient mice to a murine model of experimental lung metastasis. In this model, B16F10 murine melanoma cells are injected into the tail vein resulting in multiple lung metastases within 20 days. Both hemi- and homozygous factor VIII deficient mice were protected against lung metastasis compared to wild-type littermate controls. In contrast, homozygous factor V Leiden mice developed more metastases than wild-type littermates, whereas heterozygous carriers showed an intermediate number of pulmonary foci. Overall, these data show that a congenital susceptibility to either bleeding or thrombosis modifies the metastatic capacity of cancer cells in the bloodstream and suggest that procoagulant phenotypes are a risk factor for tumour metastasis. PMID:18363839

  10. A case report of gastric cancer with brain metastasis: Rare peripheral nervous system symptoms

    PubMed Central

    YANG, GE-LIANG; LUO, TIAN-HANG; ZHANG, HUI-QING; LING, CHANG-QUAN; LI, BAI

    2016-01-01

    Gastric cancer with brain metastasis is rare. The present study reports a case of gastric cancer with isolated brain metastasis 1 year after gastrectomy. To the best of our knowledge, there have been no prior reports of solitary brain metastasis from gastric cancer with peripheral nervous system symptoms. A distal gastrectomy was performed on a 60-year-old male patient with gastric cancer in November 2012. Postoperative pathological analysis revealed a moderately differentiated adenocarcinoma with tumor invasion into the serosa and metastasis to one dissected lymph node. No abnormalities were found at follow-up examination. However, a tumor representing metastasis to the brain was recognized by a cranial enhanced magnetic resonance imaging examination 1 year after gastrectomy, which was performed when the patient exhibited numbness and thigmesthesia. The patient was administered 30 Gy of stereotactic radiotherapy, delivered in 5 fractions. The patient succumbed to disease 10 months subsequent to undergoing radiotherapy. This case report suggests that gastric cancer may re-present as brain metastasis with peripheral nervous system symptoms. PMID:27073571

  11. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells.

    PubMed

    Olkhanud, Purevdorj B; Baatar, Dolgor; Bodogai, Monica; Hakim, Fran; Gress, Ronald; Anderson, Robin L; Deng, Jie; Xu, Mai; Briest, Susanne; Biragyn, Arya

    2009-07-15

    Cancer metastasis is a leading cause of cancer morbidity and mortality. More needs to be learned about mechanisms that control this process. In particular, the role of chemokine receptors in metastasis remains controversial. Here, using a highly metastatic breast cancer (4T1) model, we show that lung metastasis is a feature of only a proportion of the tumor cells that express CCR4. Moreover, the primary tumor growing in mammary pads activates remotely the expression of TARC/CCL17 and MDC/CCL22 in the lungs. These chemokines acting through CCR4 attract both tumor and immune cells. However, CCR4-mediated chemotaxis was not sufficient to produce metastasis, as tumor cells in the lung were efficiently eliminated by natural killer (NK) cells. Lung metastasis required CCR4(+) regulatory T cells (Treg), which directly killed NK cells using beta-galactoside-binding protein. Thus, strategies that abrogate any part of this process should improve the outcome through activation of effector cells and prevention of tumor cell migration. We confirm this prediction by killing CCR4(+) cells through delivery of TARC-fused toxins or depleting Tregs and preventing lung metastasis. PMID:19567680

  12. Host Cxcr2-dependent regulation of mammary tumor growth and metastasis

    PubMed Central

    Sharma, Bhawna; Nannuru, Kalyan C.; Varney, Michelle L.

    2016-01-01

    Host-derived angiogenic and inflammatory tumor supportive microenvironment regulates progression and metastasis, but the molecular mechanism(s) underlying host-tumor interactions remains unclear. Tumor expression of CXCR2 and its ligands have been shown to regulate angiogenesis, invasion, tumor growth, and metastasis. In this report, we hypothesized that host-derived Cxcr2-dependent signaling plays an important role in breast cancer growth and metastasis. Two mammary tumor cell lines Cl66 and 4T1 cells were orthotopically implanted into the mammary fat pad of wild-type and Cxcr2−/− female BALB/c mice. Tumor growth and spontaneous lung metastasis were monitored. Immunohistochemical analyses of the tumor tissues were performed to analyze proliferation, angiogenesis, apoptosis and immune cell infiltration. Our results demonstrated that knock-down of host Cxcr2 decreases tumor growth and metastasis by reducing angiogenesis, proliferation and enhancing apoptosis. Host Cxcr2 plays an important role in governing the pro-inflammatory response in mammary tumors as evaluated by decreased Gr1+ tumor-associated granulocytes, F4/80+ tumor associated macrophages, and CD11b+Gr1+ myeloid derived suppressor cells in Cxcr2−/− mice as compared to control wild-type mice. Together, these results demonstrate that host Cxcr2-dependent signaling regulates mammary tumor growth and metastasis by promoting angiogenesis and pro-inflammatory responses. PMID:25511644

  13. Medullary metastasis of a malignant peripheral nerve sheath tumor: A case report

    PubMed Central

    Hagi, Tomohito; Nakamura, Tomoki; Yokoji, Ayumu; Matsumine, Akihiko; Sudo, Akihiro

    2016-01-01

    The present study reports a case of medullary metastasis without lung metastasis that occurred as a result of a malignant peripheral nerve sheath tumor (MPNST). An 81-year-old woman presented with a MPNST in the left brachial plexus, arising from the cervical nerve root. The patient underwent carbon ion radiotherapy; however, tumor recurrence was identified in the left shoulder. Subsequently, the patient underwent wide excision. Three weeks subsequent to surgery, imbalance and dysarthria developed suddenly. Dysphagia emerged and left upper limb pain disappeared on the day after symptom development. Magnetic resonance imaging (MRI) revealed that this was due to metastasis to the medulla. Five days subsequent to the onset of dysarthria, the patient succumbed due to respiratory failure. To the best of our knowledge, no previous cases of medullary metastasis arising from a MPNST in the absence of lung metastasis have been reported. MRI is a useful examination tool for the identification of brain metastases; however, the high cost of MRI as a routine examination must be considered due to the rarity of brain metastases. Therefore, methods to detect brain metastasis warrant further investigation. PMID:27588138

  14. Clusterin induced by N,N′-Dinitrosopiperazine is involved in nasopharyngeal carcinoma metastasis

    PubMed Central

    Wang, Weiwei; Tan, Gongjun; Zhang, Zhenlin; Dong, Zigang; Kang, Tiebang; Tang, Faqing

    2016-01-01

    Nasopharyngeal carcinoma (NPC) has a high metastatic clinicopathological feature. As a carcinogen factor, N,N′-Dinitrosopiperazine (DNP) is involved in NPC metastasis, but its precise mechanism has not been fully elucidated. Herein, we showed that DNP promotes NPC metastasis through up-regulating anterior clusterin (CLU). DNP was found to increase CLU, matrix metalloproteinases (MMP) 9 and vascular endothelial growth factor (VEGF) expression and activity, further DNP-increased MMP-9 and VEGF expression was through up-regulating CLU. We also found that DNP increased the binding of CLU with MMP-9 or VEGF. DNP induced the motility and invasion of NPC cell, which was inhibited by siRNA-CLU. The clinical investigation showed that CLU, MMP-9 and VEGF were positively correlated with the tumor-node -metastasis (TNM) classification. These results indicate that DNP may promote NPC tumor metastasis through up-regulating CLU, MMP-9 and VEGF expression. Therefore, DNP-increased CLU expression may be an important factor of NPC-high metastasis, and CLU may serve as a biomarker for NPC metastasis. PMID:26716898

  15. THE MRI FINDINGS OF IRIS METASTASIS IN PATIENTS WITH BREAST CANCER

    PubMed Central

    Mutlu, Hasan; Akça, Zeki; Büyükçelik, Abdullah; Öztürk, Mustafa; Taşdemir, Mustafa; Kubilay Yazıcıoğlu, Alper; Kaplan, Bünyamin; Uçar, Kadir

    2012-01-01

    Breast cancer and lung cancer are the most common tumors that metastasize to iris. The metastasis of iris was generally diagnosed on ophthalmologic examination. In this case, we reported iris metastasis of patients with adenocarcinoma of breast cancer and MRI findings. We report a case of a 51-year-old. She was diagnosed breast cancer two years ago. After adjuvant chemotherapy, radiotherapy and trastuzumab, she was admitted to hospital with the complaints of headache on February 2012. The magnetic resonance imaging (MRI ) revealed multiple brain metastasis. Whole brain radiotherapy and palliative chemotherapy were applied to the patients. In follow-up, on ophthalmological examination, there was a solid lesion on iris. The orbital MRI was performed and it revealed the thickness on iris of left eye. After diagnostic procedure final pathological rewiev reported that invasive ductal carcinom metastasis. Iris metastasis may be considered by MRI findings following: The thickness on iris and contrast enhanced lesion. This reason may be resulted that the fine niddle aspiration biopsy for diagnosis of iris metastasis is not need. PMID:23378695

  16. Blocking the Adhesion Cascade at the Premetastatic Niche for Prevention of Breast Cancer Metastasis

    PubMed Central

    Kang, Shin-Ae; Hasan, Nafis; Mann, Aman P; Zheng, Wei; Zhao, Lichao; Morris, Lynsie; Zhu, Weizhu; Zhao, Yan D; Suh, K Stephen; Dooley, William C; Volk, David; Gorenstein, David G; Cristofanilli, Massimo; Rui, Hallgeir; Tanaka, Takemi

    2015-01-01

    Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)–/CD44+ hormone-independent breast cancer cells, but not of the ER+/CD44-/low hormone-dependent breast cancer cells. Coincidentally, CD44+ breast cancer cells were abundant in metastatic lung and brain lesions in ER– breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER–/CD44+ breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44+ cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER–/CD44+ breast cancer. PMID:25815697

  17. Difficult Diagnosis of Colon Adenocarcinoma Metastasis to Retina: A Case Report and Literature Review

    PubMed Central

    Nookala, Ratnam; Batchu, Vera V; Lee, Heather M; Loghmani, Amir; Chhabra, Gurdeep S

    2016-01-01

    Intraocular metastatic tumors have been increasingly reported in the recent past. Unlike choroidal metastasis, metastasis to retina is very rare and so far has been reported in very few case reports only. A 56 year-old male who presented with a history of adenocarcinoma of the cecum and underwent lap colectomy for the primary cecal tumor, received adjuvant chemotherapy for a year after surgery and decided to stop. He was also diagnosed with metastasis to liver and lung at this time. He presented with left eye pain, pressure and decreased vision suspicious for retinal metastasis from cecal primary lesion, 2 years after initial diagnosis. A mass of 5 x 10 mm was found on ophthalmoscopic examination and on ultrasound of the eye, in spite of normal results of MRI of the orbit. Palliative radiation therapy of the left eye resulted in decreased eye pressure and improved vision. As retinal metastasis carries a poorer prognosis due to higher risk of spread to central nervous system, the diagnosis of retinal metastasis in case of gastrointestinal cancers patients who present with vision changes should be made urgently. These patients should be thoroughly investigated with a synergistic approach of opthalmoscopic examination, ultrasound of the eye along with other imaging modalities like MRI of the orbit and just not MRI of orbit. Immediate action in the form of surgical or radiation treatments of the metastatic tumors of the eye should be instituted early on for a better prognosis. PMID:27489594

  18. VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice.

    PubMed

    Ferjančič, Špela; Gil-Bernabé, Ana M; Hill, Sally A; Allen, Philip D; Richardson, Peter; Sparey, Tim; Savory, Edward; McGuffog, Jane; Muschel, Ruth J

    2013-04-18

    Pulmonary metastasis is a frequent cause of poor outcome in cancer patients. The formation of pulmonary metastasis is greatly facilitated by recruitment of myeloid cells, which are crucial for tumor cell survival and extravasation. During inflammation, homing of myeloid cells is mediated by endothelial activation, raising the question of a potential role for endothelial activation in myeloid cell recruitment during pulmonary metastasis. Here, we show that metastatic tumor cell attachment causes the induction of the endothelial activation markers vascular cell adhesion molecule-1 (VCAM-1) and vascular adhesion protein-1 (VAP-1). Induction of VCAM-1 is dependent on tumor cell-clot formation, decreasing upon induction of tissue factor pathway inhibitor or treatment with hirudin. Furthermore, inhibition of endothelial activation with a VCAM-1 blocking antibody or a VAP-1 small molecule inhibitor leads to reduced myeloid cell recruitment and diminished tumor cell survival and metastasis without affecting tumor cell adhesion. Simultaneous inhibition of VCAM-1 and VAP-1 does not result in further reduction in myeloid cell recruitment and tumor cell survival, suggesting that both act through closely related mechanisms. These results establish VCAM-1 and VAP-1 as mediators of myeloid cell recruitment in metastasis and identify VAP-1 as a potential target for therapeutic intervention to combat early metastasis.

  19. SPA-1 controls the invasion and metastasis of human prostate cancer.

    PubMed

    Shimizu, Yosuke; Hamazaki, Yoko; Hattori, Masakazu; Doi, Keiko; Terada, Naoki; Kobayashi, Takashi; Toda, Yoshinobu; Yamasaki, Toshinari; Inoue, Takahiro; Kajita, Yoichiro; Maeno, Atsushi; Kamba, Tomomi; Mikami, Yoshiki; Kamoto, Toshiyuki; Yamada, Tomomi; Kanno, Toru; Yoshikawa, Kiyotsugu; Ogawa, Osamu; Minato, Nagahiro; Nakamura, Eijiro

    2011-04-01

    Recent studies suggest that SIPA1 encoding a Rap GTPase-activating protein SPA-1 is a candidate metastasis efficiency-modifying gene in human breast cancer. In this study, we investigated the expression and function of SPA-1 in human prostate cancer (CaP). Immunohistochemical studies of tumor specimens from CaP patients revealed a positive correlation of SPA-1 expression with disease progression and metastasis. The correlation was recapitulated in human CaP cell lines; LNCaP that rarely showed metastasis in SCID mice expressed an undetectable level of SPA-1, whereas highly metastatic PC3 showed abundant SPA-1 expression. Moreover, SIPA1 transduction in LNCaP caused prominent abdominal lymph node metastasis without affecting primary tumor size, whereas shRNA-mediated SIPA1 knockdown or expression of a dominant-active Rap1 mutant (Rap1V12) in PC3 suppressed metastasis. LNCaP transduced with SPA-1 (LNCaP/SPA-1) showed attenuated adhesion to the precoated extracellular matrices (ECM) including collagens and fibronectin, due to defective ECM-medicated Rap1 activation. In addition, LNCaP/SPA-1 showed a diminished level of nuclear Brd4, which is known to bind SPA-1, resulting in reduced expression of a series of ECM-related genes. These results suggest that SPA-1 plays an important role in controlling metastasis efficiency of human CaP by regulating the expression of and interaction with ECM in the primary sites.

  20. NSG Mice Provide a Better Spontaneous Model of Breast Cancer Metastasis than Athymic (Nude) Mice

    PubMed Central

    Puchalapalli, Madhavi; Zeng, Xianke; Mu, Liang; Anderson, Aubree; Hix Glickman, Laura; Zhang, Ming; Sayyad, Megan R.; Mosticone Wangensteen, Sierra; Clevenger, Charles V.; Koblinski, Jennifer E.

    2016-01-01

    Metastasis is the most common cause of mortality in breast cancer patients worldwide. To identify improved mouse models for breast cancer growth and spontaneous metastasis, we examined growth and metastasis of both estrogen receptor positive (T47D) and negative (MDA-MB-231, SUM1315, and CN34BrM) human breast cancer cells in nude and NSG mice. Both primary tumor growth and spontaneous metastases were increased in NSG mice compared to nude mice. In addition, a pattern of metastasis similar to that observed in human breast cancer patients (metastases to the lungs, liver, bones, brain, and lymph nodes) was found in NSG mice. Furthermore, there was an increase in the metastatic burden in NSG compared to nude mice that were injected with MDA-MB-231 breast cancer cells in an intracardiac experimental metastasis model. This data demonstrates that NSG mice provide a better model for studying human breast cancer metastasis compared to the current nude mouse model. PMID:27662655

  1. A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma

    PubMed Central

    Mirabello, Lisa; Koster, Roelof; Moriarity, Branden S.; Spector, Logan G.; Meltzer, Paul S.; Gary, Joy; Machiela, Mitchell J.; Pankratz, Nathan; Panagiotou, Orestis A.; Largaespada, David; Wang, Zhaoming; Gastier-Foster, Julie M.; Gorlick, Richard; Khanna, Chand; de Toledo, Silvia Regina Caminada; Petrilli, Antonio S.; Patiño-Garcia, Ana; Sierrasesúmaga, Luis; Lecanda, Fernando; Andrulis, Irene L.; Wunder, Jay S.; Gokgoz, Nalan; Serra, Massimo; Hattinger, Claudia; Picci, Piero; Scotlandi, Katia; Flanagan, Adrienne M.; Tirabosco, Roberto; Amary, Maria Fernanda; Halai, Dina; Ballinger, Mandy L.; Thomas, David M.; Davis, Sean; Barkauskas, Donald A.; Marina, Neyssa; Helman, Lee; Otto, George M.; Becklin, Kelsie L.; Wolf, Natalie K.; Weg, Madison T.; Tucker, Margaret; Wacholder, Sholom; Fraumeni, Joseph F.; Caporaso, Neil E.; Boland, Joseph F.; Hicks, Belynda D.; Vogt, Aurelie; Burdett, Laurie; Yeager, Meredith; Hoover, Robert N.; Chanock, Stephen J.; Savage, Sharon A.

    2015-01-01

    Metastasis is the leading cause of death in osteosarcoma patients, the most common pediatric bone malignancy. We conducted a multi-stage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified a SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P=1.2×10−9, OR 2.43, 95% CI 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. Additionally, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib, and had lowered Nfib expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis, and that NFIB is an osteosarcoma metastasis susceptibility gene. PMID:26084801

  2. Analysis of Predictors for Lymph Node Metastasis in Patients with Superficial Esophageal Carcinoma

    PubMed Central

    Jia, Ruzhen; Luan, Qinsong; Wang, Jing; Hou, Dongsheng

    2016-01-01

    In order to predict related risk factors for lymph node metastasis (LNM) in patients with superficial esophageal carcinoma (SEC) and provide reference for endoscopic minimally invasive treatment, we included a total of 93 patients with superficial esophageal carcinoma who have underwent esophagectomy and lymph node dissection from 2010 to 2015. The depth of invasion was remeasured and classified into 6 groups according to their wall penetration. The prediction model was founded based on the independent risk factors. The results shows that lymph node metastasis of m1, m2, m3, sm1, sm2, and sm3 of superficial esophageal carcinoma was 0%, 0%, 5.3%, 8.7%, 17.6%, and 37.5%, respectively. The tumor size, differentiation, and lymphvascular invasion were also significantly related to lymph node metastasis by univariate analysis. Multivariate analysis showed that the depth of invasion and lymphovascular invasion were independent risk factors of lymph node metastasis. A prediction model for lymph node metastasis was established as follows: p = ex/(1 + ex), and x = −5.469 + 0.839 × depth of invasion + 1.992 × lymphavascular metastasis. The area under ROC curve was 0.858 (95% CI: 0.757–0.959). It was also shown that the depth of invasion was related to tumor differentiation, macroscopic type, and tumor size. PMID:27799939

  3. A novel gene expression signature for bone metastasis in breast carcinomas.

    PubMed

    Savci-Heijink, C Dilara; Halfwerk, Hans; Koster, Jan; van de Vijver, Marc J

    2016-04-01

    Metastatic cancer remains the leading cause of death for patients with breast cancer. To understand the mechanisms underlying the development of distant metastases to specific sites is therefore important and of potential clinical value. From 157 primary breast tumours of the patients with known metastatic disease, gene expression profiling data were generated and correlated to metastatic behaviour including site-specific metastasis, metastasis pattern and survival outcomes. We analysed gene expression signatures specifically associated with the development of bone metastases. As a validation cohort, we used a published dataset of 376 breast carcinomas for which gene expression data and site-specific metastasis information were available. 80.5 % of luminal-type tumours developed bone metastasis as opposed to 41.7 % of basal and 55.6 % of HER2-like tumours. A novel 15-gene signature identified 82.4 % of the tumours with bone metastasis, 85.2 % of the tumours which had bone metastasis as first site of metastasis and 100 % of the ones with bone metastasis only (p 9.99e-09), in the training set. In the independent dataset, 81.2 % of the positive tested tumours had known metastatic disease to the bone (p 4.28e-10). This 15-gene signature showed much better correlation with the development of bone metastases than previously identified signatures and was predictive in both ER-positive as well as in ER-negative tumours. Multivariate analyses revealed that together with the molecular subtype, our 15-gene expression signature was significantly correlated to bone metastasis status (p <0.001, 95 % CI 3.86-48.02 in the training set; p 0.001, 95 % CI 1.54-5.00 in the independent set). The 15 genes, APOPEC3B, ATL2, BBS1, C6orf61, C6orf167, MMS22L, KCNS1, MFAP3L, NIP7, NUP155, PALM2, PH-4, PGD5, SFT2D2 and STEAP3, encoded mainly membrane-bound molecules with molecular function of protein binding. The expression levels of the up-regulated genes (NAT1, BBS1 and PH-4) were

  4. Features and prognostic impact of distant metastasis in patients with stage IV lung adenocarcinoma harboring EGFR mutations: importance of bone metastasis.

    PubMed

    Fujimoto, Daichi; Ueda, Hiroyuki; Shimizu, Ryoko; Kato, Ryoji; Otoshi, Takehiro; Kawamura, Takahisa; Tamai, Koji; Shibata, Yumi; Matsumoto, Takeshi; Nagata, Kazuma; Otsuka, Kyoko; Nakagawa, Atsushi; Otsuka, Kojiro; Katakami, Nobuyuki; Tomii, Keisuke

    2014-06-01

    Mutated epidermal growth factor receptor (EGFR) and signaling pathways were associated with multiple brain and intra-pulmonary metastases, oncogenic progression and metastasis. However, features of metastasis to other organs and the independent prognostic influence of metastatic lesions were not elucidated in patients with lung cancer harboring EGFR mutations. Between January 2007 and April 2012, we treated 277 patients diagnosed with stage IV lung adenocarcinoma. Studied were 246 patients with available tumor EGFR mutation data who also underwent radiographic evaluation of lung, abdominal, brain, and bone metastases. The EGFR mutated group (N = 98) had significantly more metastatic lesions in the brain and bone than the wild-type group (N = 148): brain, 3 (1-93) versus 2 (1-32) median (range), P = 0.023; bone, 3 (1-43) versus 2 (1-27), P = 0.035, respectively. In addition, EGFR mutations were significantly more frequent in patients with multiple than non-multiple lung metastases (24/40 vs. 12/42, P = 0.004). Multivariate analysis showed that bone metastasis was a significant independent negative predictive factor of overall survival (OS) in patients with mutated [hazard ratio (HR) 2.04; 95 % confidence interval (CI) 1.17-3.64; P = 0.011] and wild-type EGFR (HR 2.09; 95 % CI 1.37-3.20; P < 0.001). In conclusion, patients with mutated EGFR had more lung, brain, and bone metastases, and bone metastasis was an independent negative predictor of OS.

  5. Identification of metastasis-associated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1.

    PubMed

    Wang, Jian-Wei; Peng, Shu-You; Li, Jiang-Tao; Wang, Yong; Zhang, Zhi-Ping; Cheng, Yan; Cheng, De-Qing; Weng, Wei-Hong; Wu, Xiang-Song; Fei, Xiao-Zhou; Quan, Zhi-Wei; Li, Ji-Yu; Li, Song-Gang; Liu, Ying-Bin

    2009-08-18

    Advanced gallbladder cancer has an extremely poor prognosis because of metastasis. Identification of metastasis-related biomarkers is essential to improve patient survival. In the present study, metastasis-associated proteins were identified by comparative proteomic analysis and the metastasis-related function of the candidate protein, chloride intracellular channel 1 (CLIC1), was further elucidated. Two cell lines with high or low metastatic potential (termed GBC-SD18H and GBC-SD18L, respectively), originating from the same parental gallbladder carcinoma GBC-SD cell line, were identified by spontaneous metastasis in vivo and characterized by metastatic phenotypes analysis in vitro. Subsequently, a proteomic approach comprised of two-dimensional gel electrophoresis analysis and mass spectroscopy was used to identify and compare the protein expression patterns between GBC-SD18L and GBC-SD18H. Twenty-six proteins were identified and further verified by one-dimensional Western blotting and semiquantitative reverse transcriptase polymerase chain reaction analysis. It was determined that CLIC1, ezrin, vimentin, annexin A3, WD repeat domain 1, triosephosphate isomerase, C1-tetrahydrofolate synthase, Rho GDP-dissociation inhibitor 1, T-complex protein 1, heterogeneous nuclear ribonucleoprotein K, glutamate dehydrogenase 1, proteasome activator complex subunit 3 and Rab GDP-dissociation inhibitor beta were significantly up-regulated in the highly metastatic GBC-SD18H cell line compared to the poorly metastatic GBC-SD18L cell line. However, phosphoglycerate kinase 1 and programmed cell death protein 8 were significantly down-regulated in the highly metastatic GBC-SD18H cell line compared to GBC-SD18L. Considering that CLIC1 was profuse in highly metastatic GBC-SD18H but scarce in poorly metastatic GBC-SD18L, the association of CLIC1 with metastasis was further elucidated by the overexpression and RNA interference of CLIC1 in GBC-SD18L cells and GBC-SD18H cells, respectively

  6. All-human microphysical model of metastasis therapy.

    PubMed

    Wheeler, Sarah E; Borenstein, Jeffrey T; Clark, Amanda M; Ebrahimkhani, Mohammad R; Fox, Ira J; Griffith, Linda; Inman, Walker; Lauffenburger, Douglas; Nguyen, Transon; Pillai, Venkateswaran C; Prantil-Baun, Rachelle; Stolz, Donna B; Taylor, Donald; Ulrich, Theresa; Venkataramanan, Raman; Wells, Alan; Young, Carissa

    2013-01-01

    The vast majority of cancer mortalities result from distant metastases. The metastatic microenvironment provides unique protection to ectopic tumors as the primary tumors often respond to specific agents. Although significant interventional progress has been made on primary tumors, the lack of relevant accessible model in vitro systems in which to study metastases has plagued metastatic therapeutic development--particularly among micrometastases. A real-time, all-human model of metastatic seeding and cancer cells that recapitulate metastatic growth and can be probed in real time by a variety of measures and challenges would provide a critical window into the pathophysiology of metastasis and pharmacology of metastatic tumor resistance. To achieve this we are advancing our microscale bioreactor that incorporates human hepatocytes, human nonparenchymal liver cells, and human breast cancer cells to mimic the hepatic niche in three dimensions with functional tissue. This bioreactor is instrumented with oxygen sensors, micropumps capable of generating diurnally varying profiles of nutrients and hormones, while enabling real-time sampling. Since the liver is a major metastatic site for a wide variety of carcinomas and other tumors, this bioreactor uniquely allows us to more accurately recreate the human metastatic microenvironment and probe the paracrine effects between the liver parenchyma and metastatic cells. Further, as the liver is the principal site of xenobiotic metabolism, this reactor will help us investigate the chemotherapeutic response within a metabolically challenged liver microenvironment. This model is anticipated to yield markers of metastatic behavior and pharmacologic metabolism that will enable better clinical monitoring, and will guide the design of clinical studies to understand drug efficacy and safety in cancer therapeutics. This highly instrumented bioreactor format, hosting a growing tumor within a microenvironment and monitoring its responses

  7. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer.

    PubMed

    Yang, Ying-Hua; Buhamrah, Asma; Schneider, Abraham; Lin, Yi-Ling; Zhou, Hua; Bugshan, Amr; Basile, John R

    2016-01-01

    Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects.

  8. Adaptive hypofractionated gamma knife radiosurgery for a large brainstem metastasis

    PubMed Central

    Sinclair, Georges; Bartek, Jiri; Martin, Heather; Barsoum, Pierre; Dodoo, Ernest

    2016-01-01

    Background: To demonstrate how adaptive hypofractionated radiosurgery by gamma knife (GK) can be successfully utilized to treat a large brainstem metastasis - a novel approach to a challenging clinical situation. Case Description: A 42-year-old woman, diagnosed with metastatic nonsmall cell lung cancer in July 2011, initially treated with chemotherapy and tyrosine kinase inhibitors, developed multiple brain metastases March 2013, with subsequent whole brain radiotherapy, after which a magnetic resonance imaging (MRI) showed a significant volume regression of all brain metastases. A follow-up MRI in October 2013 revealed a growing brainstem lesion of 26 mm. Linear accelerator-based radiotherapy and microsurgery were judged contraindicated, why the decision was made to treat the patient with three separate radiosurgical sessions during the course of 1 week, with an 18% tumor volume reduction demonstrated after the last treatment. Follow-up MRI 2.5 months after her radiosurgical treatment showed a tumor volume reduction of 67% compared to the 1st day of treatment. Later on, the patient developed a radiation-induced perilesional edema although without major clinical implications. An MRI at 12 months and 18-fluoro-deoxyglucose positron emission tomography of the brain at 13 months showed decreased edema with no signs of tumor recurrence. Despite disease progression during the last months of her life, the patient's condition remained overall acceptable. Conclusion: GK-based stereotactic adaptive hypofractionation proved to be effective to achieve tumor control while limiting local adverse reactions. This surgical modality should be considered when managing larger brain lesions in critical areas. PMID:26958430

  9. Metformin may protect nondiabetic breast cancer women from metastasis.

    PubMed

    El-Haggar, Sahar Mohammed; El-Shitany, Nagla A; Mostafa, Mohamed Farouk; El-Bassiouny, Noha Ahmed

    2016-04-01

    Metformin, a widely prescribed oral hypoglycemic agent, has recently received a big interest because of its potential antitumorigenic effects in different cancer types. The present study investigated the impact of adding metformin to breast cancer adjuvant therapy in nondiabetic women on, insulin like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), insulin, fasting blood glucose (FBG), the molar ratio of IGF-1 to IGFBP-3, homeostatic model assessment of insulin resistance (HOMA-IR) and metastasis. 102 women with newly diagnosed breast cancer were divided into 2 main groups, a control group and a metformin group. All women were treated with adjuvant therapy, according to the protocols of Ministry of Health and Population and National Cancer Institute, Egypt. Moreover, the women in the metformin group received 850 mg of metformin twice daily. Blood samples were collected at baseline, after chemotherapy (CT), after 6 months of hormonal therapy (6-HT) and 12 months of hormonal therapy (12-HT) for analysis of serum IGF-1, IGFBP-3, insulin, FBG and cancer antigen 15-3 (CA15-3). Metformin resulted in a significant reduction of IGF-1, IGF-1: IGFBP-3 molar ratio, insulin, FBG and HOMA-IR. On the other hand, metformin caused a significant increase of IGFBP-3. Moreover, metformin significantly decreased the numbers of metastatic cases after 6-HT. Metformin may have potential antitumor and antimetastatic effects that need further clinical investigations. This may be attributed to either the significant increase of the apoptotic inducer IGFBP-3 or/and the significant reduction of mitogenic insulin, IGF-1, free bioactive IGF-1, FBG and HOMA-IR. PMID:26902691

  10. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer

    PubMed Central

    Yang, Ying-Hua; Buhamrah, Asma; Schneider, Abraham; Lin, Yi-Ling; Zhou, Hua; Bugshan, Amr; Basile, John R.

    2016-01-01

    Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects. PMID:26910109

  11. Host b7x promotes pulmonary metastasis of breast cancer.

    PubMed

    Abadi, Yael M; Jeon, Hyungjun; Ohaegbulam, Kim C; Scandiuzzi, Lisa; Ghosh, Kaya; Hofmeyer, Kimberly A; Lee, Jun Sik; Ray, Anjana; Gravekamp, Claudia; Zang, Xingxing

    2013-04-01

    B7x (B7-H4 or B7S1) is an inhibitory member of the B7 family of T cell costimulation. It is expressed in low levels in healthy peripheral tissues, such as the lung epithelium, but is overexpressed in a variety of human cancers with negative clinical associations, including metastasis. However, the function of B7x in the context of cancer, whether expressed on cancer cells or on surrounding "host" tissues, has not been elucidated in vivo. We used the 4T1 metastatic breast cancer model and B7x knockout (B7x (-/-)) mice to investigate the effect of host tissue-expressed B7x on cancer. We found that 4T1 cells were B7x negative in vitro and in vivo, and B7x(-/-) mice had significantly fewer lung 4T1 tumor nodules than did wild-type mice. Furthermore, B7x(-/-) mice showed significantly enhanced survival and a memory response to tumor rechallenge. Mechanistic studies revealed that the presence of B7x correlated with reduced general and tumor-specific T cell cytokine responses, as well as with an increased infiltration of immunosuppressive cells, including tumor-associated neutrophils, macrophages, and regulatory T cells, into tumor-bearing lungs. Importantly, tumor-associated neutrophils strongly bound B7x protein and inhibited the proliferation of both CD4 and CD8 T cells. These results suggest that host B7x may enable metastasizing cancer cells to escape local antitumor immune responses through interactions with the innate and adaptive immune systems. Thus, targeting the B7x pathway holds much promise for improving the efficacy of immunotherapy for metastatic cancer. PMID:23455497

  12. Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis.

    PubMed

    Liu, Gang; Lu, Shengjun; Wang, Xuanjun; Page, Stephanie T; Higano, Celestia S; Plymate, Stephen R; Greenberg, Norman M; Sun, Shaoli; Li, Zihai; Wu, Jennifer D

    2013-10-01

    The activating receptor NK cell group 2 member D (NKG2D) mediates antitumor immunity in experimental animal models. However, whether NKG2D ligands contribute to tumor suppression or progression clinically remains controversial. Here, we have described 2 novel lines of "humanized" bi-transgenic (bi-Tg) mice in which native human NKG2D ligand MHC class I polypeptide-related sequence B (MICB) or the engineered membrane-restricted MICB (MICB.A2) was expressed in the prostate of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous carcinogenesis. Bi-Tg TRAMP/MICB mice exhibited a markedly increased incidence of progressed carcinomas and metastasis, whereas TRAMP/MICB.A2 mice enjoyed long-term tumor-free survival conferred by sustained NKG2D-mediated antitumor immunity. Mechanistically, we found that cancer progression in TRAMP/MICB mice was associated with loss of the peripheral NK cell pool owing to high serum levels of tumor-derived soluble MICB (sMICB). Prostate cancer patients also displayed reduction of peripheral NK cells and high sMIC levels. Our study has not only provided direct evidence in "humanized" mouse models that soluble and membrane-restricted NKG2D ligands pose opposite impacts on cancer progression, but also uncovered a mechanism of sMIC-induced impairment of NK cell antitumor immunity. Our findings suggest that the impact of soluble NKG2D ligands should be considered in NK cell-based cancer immunotherapy and that our unique mouse models should be valuable for therapy optimization. PMID:24018560

  13. Dietary energy balance modulates ovarian cancer progression and metastasis.

    PubMed

    Al-Wahab, Zaid; Tebbe, Calvin; Chhina, Jasdeep; Dar, Sajad A; Morris, Robert T; Ali-Fehmi, Rouba; Giri, Shailendra; Munkarah, Adnan R; Rattan, Ramandeep

    2014-08-15

    A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.

  14. IGFBP-3 is a Metastasis Suppression Gene in Prostate Cancer

    PubMed Central

    Mehta, Hemal H.; Gao, Qinglei; Galet, Colette; Paharkova, Vladislava; Wan, Junxiang; Said, Jonathan; Sohn, Joanne J.; Lawson, Gregory; Cohen, Pinchas; Cobb, Laura J.; Lee, Kuk-Wha

    2011-01-01

    The insulin-like growth factor binding protein IGFBP-3 is a pro-apoptotic and anti-angiogenic protein in prostate cancer (CaP). Epidemiological studies suggest that low IGFBP-3 is associated with greater risk of aggressive, metastatic prostate cancers, but in vivo functional data are lacking. Here we show that mice that are genetically deficient in IGFBP-3 exhibit weaker growth of primary prostate tumors growth but higher incidence of metastatic disease. Prostates in IGFBP-3 knockout mice (IGFBP-3KO mice) failed to undergo apoptosis after castration. Spontaneous prostate tumors did not develop in IGFBP-3KO mice, but splenic lymphomas occured in 23% of female IGFBP-3KO mice by 80 weeks of age. To assess the effects of IGFBP-3 deficiency on prostate cancer development, we crossed IGFBP-3KO mice with a c-Myc-driven model of CaP that develops slow-growing, non-metastatic tumors. By 24 weeks of age, well-differentiated prostate cancers were observed in all mice regardless of IGFBP-3 status. However, by 80 weeks of age IGFBP-3KO mice tended to exhibit larger prostate tumors than control mice. More strikingly, lung metastases were observed at this time in 55% of the IGFBP-3KO mice but none of the control animals. Cell lines established from Myc:IGFBP-3KO tumors displayed more aggressive phenotypes in proliferation, invasion and colony formation assays, relative to control Myc tumor cell lines. In addition, Myc:IGFBP-3KO cells exhibited evidence of epithelial-mesenchymal transition (EMT). Our findings establish a function for IGFBP-3 in suppressing metastasis in prostate cancer, and they also offer the first reported transgenic model of spontaneous metastatic prostate cancer for studies of this advanced stage of disease. PMID:21697285

  15. MicroRNA Profiles Discriminate among Colon Cancer Metastasis

    PubMed Central

    Drusco, Alessandra; Nuovo, Gerard J.; Zanesi, Nicola; Di Leva, Gianpiero; Pichiorri, Flavia; Volinia, Stefano; Fernandez, Cecilia; Antenucci, Anna; Costinean, Stefan; Bottoni, Arianna; Rosito, Immacolata A.; Liu, Chang-Gong; Burch, Aaron; Acunzo, Mario; Pekarsky, Yuri; Alder, Hansjuerg; Ciardi, Antonio; Croce, Carlo M.

    2014-01-01

    MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC). In most cases, metastatic disease is difficult to predict and to prevent with adequate therapies. The aim of our study was to identify a microRNA signature for metastatic CRC that could predict and differentiate metastatic target organ localization. Normal and cancer tissues of three different groups of CRC patients were analyzed. RNA microarray and TaqMan Array analysis were performed on 66 Italian patients with or without lymph nodes and/or liver recurrences. Data obtained with the two assays were analyzed separately and then intersected to identify a primary CRC metastatic signature. Five differentially expressed microRNAs (hsa-miR-21, -103, -93, -31 and -566) were validated by qRT-PCR on a second group of 16 American metastatic patients. In situ hybridization was performed on the 16 American patients as well as on three distinct commercial tissues microarray (TMA) containing normal adjacent colon, the primary adenocarcinoma, normal and metastatic lymph nodes and liver. Hsa-miRNA-21, -93, and -103 upregulation together with hsa-miR-566 downregulation defined the CRC metastatic signature, while in situ hybridization data identified a lymphonodal invasion profile. We provided the first microRNAs signature that could discriminate between colorectal recurrences to lymph nodes and liver and between colorectal liver metastasis and primary hepatic tumor. PMID:24921248

  16. RANKL: A promising circulating marker for bone metastasis response

    PubMed Central

    Ibrahim, Toni; Ricci, Marianna; Scarpi, Emanuela; Bongiovanni, Alberto; Ricci, Rossana; Riva, Nada; Liverani, Chiara; De Vita, Alessandro; La Manna, Federico; Oboldi, Devil; Serra, Patrizia; Foca, Flavia; Cecconetto, Lorenzo; Amadori, Dino; Mercatali, Laura

    2016-01-01

    Bone metastases are a frequent event in patients with solid tumors. Although great advances have been made in the treatment of these patients, the identification of novel, accurate indicators of bone response would greatly facilitate the clinical management of the disease. The receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling pathway is significantly involved in bone metastasis formation. The main aim of the present study was to evaluate the role of circulating RANK, RANKL and OPG levels in predicting bone response. Marker accuracy was also compared with that of the conventional tumor marker N-terminal telopeptide of type I collagen (NTX). A prospective study was performed on 49 patients with bone metastases from breast, lung and prostate cancer, who were undergoing treatment with zoledronic acid. Patients were monitored for 1 year with blood tests, clinical evaluation and instrumental exams according to the response evaluation criteria of the University of Texas M. D. Anderson Cancer Center (Houston, TX, USA) and the Positron Emission Tomography Response Criteria in Solid Tumors. Circulating RANK/RANKL/OPG transcripts and NTX levels were evaluated by reverse transcription-quantitative polymerase chain reaction and immune enzymatic assay, respectively. The baseline RANKL levels differed significantly between responders and non-responders, whereas no differences in NTX levels were observed between the two groups. Receiver operating characteristic curve evaluation for all markers revealed that RANKL was the most accurate marker, with an area under the curve of 0.74 (95% confidence interval, 0.54–0.93). In addition, RANKL, which is the target of the novel monoclonal antibody denosumab, was the most accurate predictor of bone response in the present series of patients with bone metastases. Thus, the use of RANKL as a marker could potentially improve clinical practice, as current bone response evaluation is still

  17. Ketone body utilization drives tumor growth and metastasis

    PubMed Central

    Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.

    2012-01-01

    We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm “two-compartment tumor metabolism.” Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav-1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco-metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes. PMID:23082722

  18. Ketone body utilization drives tumor growth and metastasis.

    PubMed

    Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2012-11-01

    We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm "two-compartment tumor metabolism." Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav-1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco-metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes. PMID:23082722

  19. RANKL: A promising circulating marker for bone metastasis response

    PubMed Central

    Ibrahim, Toni; Ricci, Marianna; Scarpi, Emanuela; Bongiovanni, Alberto; Ricci, Rossana; Riva, Nada; Liverani, Chiara; De Vita, Alessandro; La Manna, Federico; Oboldi, Devil; Serra, Patrizia; Foca, Flavia; Cecconetto, Lorenzo; Amadori, Dino; Mercatali, Laura

    2016-01-01

    Bone metastases are a frequent event in patients with solid tumors. Although great advances have been made in the treatment of these patients, the identification of novel, accurate indicators of bone response would greatly facilitate the clinical management of the disease. The receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling pathway is significantly involved in bone metastasis formation. The main aim of the present study was to evaluate the role of circulating RANK, RANKL and OPG levels in predicting bone response. Marker accuracy was also compared with that of the conventional tumor marker N-terminal telopeptide of type I collagen (NTX). A prospective study was performed on 49 patients with bone metastases from breast, lung and prostate cancer, who were undergoing treatment with zoledronic acid. Patients were monitored for 1 year with blood tests, clinical evaluation and instrumental exams according to the response evaluation criteria of the University of Texas M. D. Anderson Cancer Center (Houston, TX, USA) and the Positron Emission Tomography Response Criteria in Solid Tumors. Circulating RANK/RANKL/OPG transcripts and NTX levels were evaluated by reverse transcription-quantitative polymerase chain reaction and immune enzymatic assay, respectively. The baseline RANKL levels differed significantly between responders and non-responders, whereas no differences in NTX levels were observed between the two groups. Receiver operating characteristic curve evaluation for all markers revealed that RANKL was the most accurate marker, with an area under the curve of 0.74 (95% confidence interval, 0.54–0.93). In addition, RANKL, which is the target of the novel monoclonal antibody denosumab, was the most accurate predictor of bone response in the present series of patients with bone metastases. Thus, the use of RANKL as a marker could potentially improve clinical practice, as current bone response evaluation is still

  20. Metformin may protect nondiabetic breast cancer women from metastasis.

    PubMed

    El-Haggar, Sahar Mohammed; El-Shitany, Nagla A; Mostafa, Mohamed Farouk; El-Bassiouny, Noha Ahmed

    2016-04-01

    Metformin, a widely prescribed oral hypoglycemic agent, has recently received a big interest because of its potential antitumorigenic effects in different cancer types. The present study investigated the impact of adding metformin to breast cancer adjuvant therapy in nondiabetic women on, insulin like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), insulin, fasting blood glucose (FBG), the molar ratio of IGF-1 to IGFBP-3, homeostatic model assessment of insulin resistance (HOMA-IR) and metastasis. 102 women with newly diagnosed breast cancer were divided into 2 main groups, a control group and a metformin group. All women were treated with adjuvant therapy, according to the protocols of Ministry of Health and Population and National Cancer Institute, Egypt. Moreover, the women in the metformin group received 850 mg of metformin twice daily. Blood samples were collected at baseline, after chemotherapy (CT), after 6 months of hormonal therapy (6-HT) and 12 months of hormonal therapy (12-HT) for analysis of serum IGF-1, IGFBP-3, insulin, FBG and cancer antigen 15-3 (CA15-3). Metformin resulted in a significant reduction of IGF-1, IGF-1: IGFBP-3 molar ratio, insulin, FBG and HOMA-IR. On the other hand, metformin caused a significant increase of IGFBP-3. Moreover, metformin significantly decreased the numbers of metastatic cases after 6-HT. Metformin may have potential antitumor and antimetastatic effects that need further clinical investigations. This may be attributed to either the significant increase of the apoptotic inducer IGFBP-3 or/and the significant reduction of mitogenic insulin, IGF-1, free bioactive IGF-1, FBG and HOMA-IR.