MIT Researchers Target Cancer’s Most Deadly Phase

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Experimental lung metastasis: Image courtesy of Robert Weinberg

The Epithelial-to-Mesenchymal Transition

Embryonic tissue differentiates with a program known as the EMT, shorthand for “epithelial-to-mesenchymal transition,” which is also activated during cancer invasion and metastasis.  “The EMT enables both normal and neoplastic epithelial cells to acquire mesenchymal cells attributes such as motility, invasiveness, and a resistance to apoptosis,” Weinberg says. Carcinoma cells with mesenchymal attributes can not only physically disseminate, they can self-renew which enables them to seed new environments. Long-term exposure to stroma-associated signals also helps keep cells in the mesenchymal/stem-cell state in a self-sustaining, stable fashion.  Additionally, their resistance to programmed cell death or apoptosis is, “surely critical to the ability of the migrating cells to survive the rigors of the voyage” from primary tumors to distant sites, he adds.

Moreover, primary carcinomas, the Weinberg team’s target cancers, release signals that recruit inflammatory cells to the tumor. This both helps assemble a highly functional, tumor-supporting environment, or stroma, and keeps some of the cells in a biologically-abnormal activated state.  However, while conceptually appealing, Weinberg cautions that the role of EMT in metastasis remains unproven.

Cancer Colonization 

Pelvis with bone metastasis: Image courtesy of Diagnostic pathology

Although EMT programs seem critical for the physical dissemination of carcinoma cells, they don’t appear capable of initiating and sustaining colonization.  Colonization, Weinberg emphasizes, seems to entail a far more complex set of phenomena, and have a relatively small number of unifying general principles. The tissue microenvironment of a primary tumor is likely to differ markedly from that of a secondary site which requires the wandering cancer cell to make substantial adaptive changes in order to survive and multiply. These changes appear to be dictated by both the microenvironment of the primary tumor as well as that of the landing site.

In general, says Weinberg, colonization is an extremely inefficient process, and most cancer cells that successfully translocate from a primary to a secondary site don’t survive more than 24 hours in their new home. This is good news because the outcome of successful colonization is a rapidly expanding macrometastasis that disseminates a shower of secondary metastases. Moreover, cancer cells being dispatched from the successful new colony are likely to be invested with the kinds of genetic programs that make it easier for them to migrate and colonize a variety of tissues.  These cells are so much more fit than their ancestors that the “throngs of secondary metastases derived from the initial metastatic shower soon eclipse the initiating metastasis that spawned them,” Weinberg stresses.

Sources:

Robert A. Weinberg, Ph.D. 2011 Calloway Lecture: EMT, Cancer Stem Cells and Malignant Progression. December 14, 2011.

Chaffer, C. L., Weinberg, R. A. A Perspective on Cancer Cell Metastasis. Science: 331:1559-1564, 25 March 2011. Accessed December 24, 2011.

Mani, S. A., Guo, W., Liao Mai-Jing, et al. The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells. Cell: 133, 704-715, 16 May 2008.

Mukherjee, S. The Emperor of All Maladies: A Biography of Cancer. New York City. Scribner. (2010). ISBN 978-1-4391-0795-9.

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