Cancer Metastasis: Building a Framework

Cancer Biology and Genetics Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Cell (Impact Factor: 32.24). 12/2006; 127(4):679-95. DOI: 10.1016/j.cell.2006.11.001
Source: PubMed


How tumors spread and kill their host organism remains an enigma, but not for lack of attention. For more than a century, cancer biologists have postulated that metastasis results from the interplay of wandering tumor cells with permissive target tissues. Yet, decades of scrutiny into the molecular bases of cancer have largely focused on what causes oncogenic transformation and the incipient emergence of tumors. By comparison, the study of how tumor cells take steps toward metastasis (that is, by altering their microenvironment, entering the circulation, and colonizing a distant organ) has received less attention. Progressively, however, the idea has emerged that tumors are more than just a mass of transformed cells. A renewed focus on the problem of metastasis is now apparent, and for good reason—metastasis remains the cause of 90% of deaths from solid tumors.

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    • "Most solid tumors eventually establish colonies in distant anatomical locations; when these colonies become clinically detectable, they are called macrometastasis. While often there is a large burden from primary tumors, it is in fact metastatic disease that is responsible for most cancer fatalities [14] [37]. "
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    ABSTRACT: Metastasis is the process by which cells from a primary tumor disperse and form new tumors at distant anatomical locations. The treatment and prevention of metastatic cancer remains an extremely challenging problem. This work introduces a novel biologically motivated objective function to the radiation optimization community that takes into account metastatic risk instead of the status of the primary tumor. In this work, we consider the problem of developing fractionated irradiation schedules that minimize production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming framework is utilized to determine the optimal fractionation scheme. We evaluated our approach on a breast cancer case using the heart and the lung as organs-at-risk (OAR). For small tumor �alpha/beta� values, hypo-fractionated schedules were optimal, which is consistent with standard models. However, for relatively larger �alpha/beta� values, we found the type of schedule depended on various parameters such as the time when metastatic risk was evaluated, the alpha/beta values of the OARs, and the normal tissue sparing factors. Interestingly, in contrast to standard models, hypo-fractionated and semihypo-fractionated schedules (large initial doses with doses tapering off with time) were suggested even with large tumor �/� values. Numerical results indicate potential for significant reduction in metastatic risk.
    Physics in Medicine and Biology 10/2015; 60(22). DOI:10.1088/0031-9155/60/22/N405 · 2.76 Impact Factor
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    • "What is known is that cancer cell invasiveness initially depends on the epithelial - to - mesenchymal transition ( EMT ) , a process by which epithelial cancer cells lose their apico - basal polarity , cell - cell adhesion capacity , and gain migratory and invasive properties . Aggressive cancer cells are more invasive , owing to their ability to digest and to migrate through the extracellular matrix ( ECM ) ( Gupta and Massague , 2006 ; Friedl and Alexander , 2011 ) . Cancer cell motility relies on molecular mechanisms , such as the nucleation and polymerization of actin at the cell front , actomyosin contractility , and cycles of formation and disruption of focal adhesions . "
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    ABSTRACT: Voltage-gated sodium channels (NaV) are molecular characteristics of excitable cells. Their activation, triggered by membrane depolarization, generates transient sodium currents that initiate action potentials in neurons and muscle cells. Sodium currents were discovered by Hodgkin and Huxley using the voltage clamp technique and reported in their landmark series of papers in 1952. It was only in the 1980's that sodium channel proteins from excitable membranes were molecularly characterized by Catterall and his collaborators. Non-excitable cells can also express NaV channels in physiological conditions as well as in pathological conditions. These NaV channels can sustain biological roles that are not related to the generation of action potentials. Interestingly, it is likely that the abnormal expression of NaV in pathological tissues can reflect the re-expression of a fetal phenotype. This is especially true in epithelial cancer cells for which these channels have been identified and sodium currents recorded, while it was not the case for cells from the cognate normal tissues. In cancers, the functional activity of NaV appeared to be involved in regulating the proliferative, migrative, and invasive properties of cells. This review is aimed at addressing the non-excitable roles of NaV channels with a specific emphasis in the regulation of cancer cell biology.
    Frontiers in Pharmacology 08/2015; 6:152. DOI:10.3389/fphar.2015.00152 · 3.80 Impact Factor
    • "Tumor metastasis is estimated to account for greater than 90% of cancer-related deaths (Gupta and Massagué , 2006). Sarcomas , malignancies of mesenchymal origin, have a particular propensity for local invasion and metastatic spread. "
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    ABSTRACT: Metastatic dissemination is the leading cause of death in cancer patients, which is particularly evident for high-risk sarcomas such as Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. Previous research identified a crucial role for YB-1 in the epithelial-to-mesenchymal transition (EMT) and metastasis of epithelial malignancies. Based on clinical data and two distinct animal models, we now report that YB-1 is also a major metastatic driver in high-risk sarcomas. Our data establish YB-1 as a critical regulator of hypoxia-inducible factor 1α (HIF1α) expression in sarcoma cells. YB-1 enhances HIF1α protein expression by directly binding to and activating translation of HIF1A messages. This leads to HIF1α-mediated sarcoma cell invasion and enhanced metastatic capacity in vivo, highlighting a translationally regulated YB-1-HIF1α axis in sarcoma metastasis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 05/2015; 27(5):682-697. DOI:10.1016/j.ccell.2015.04.003 · 23.52 Impact Factor
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