If malignant cells could be kept from wandering about the body and colonizing new sites, the number of cancer deaths would be cut by about 90%. However, it’s become apparent in recent years that metastasis isn’t a simple, random process; it’s a well-orchestrated sequence of events most of which are largely unknown.
In fact, “[metastasis] remains the most poorly understood component of cancer pathogenesis,” says Robert A. Weinberg, PhD, Professor of Biology at the Massachusets Institute of Technology (MIT) in Cambridge. Professor Weinberg helped identify ras, the first human oncogene, in the 1970s and a few years later the first known tumor suppressor gene, Rb. Most recently, Weinberg’s team at the MIT Whitehead Institute for Biomedical Research created the first genetically-defined human cancer cells.
Robert A. Weinberg Discusses his Latest Research with Colleagues at the SKI in December
Understanding how metastasis works has great clinical potential and this is why, Weinberg told cancer experts at the Sloan-Kettering Institute’s President’s Research Seminar, held at the Rockefeller Research Laboratories (RRL) in New York City on December 14th, the scientists in his laboratory are vigorously investigating this “most enigmatic” aspect of cancer.
For starters, the Weinberg and colleagues have organized the complex metastatic cascade into two major parts: first, the physical translocation of a cancer cell from its primary tumor to a distant site and second, colonization. An understanding of the first step, physical dissemination, is in sight he says. However, colonization is far more complicated and may require several more years of research before the traits a cancer cell needs to implant and grow in alien soil are fully understood.
Nonetheless, knowing how a cancer cell escapes the confines of a tumor and explores adjacent environments is expected to prove important for preventing metastasis in people with early cancer lesions. Designing effective therapies for patients with already-established disease will have to wait.
“Tumor-Initiating” Cancer Stem Cells (CSCs)
“The discovery of CSCs has forced major rethinking of tumor biology,” says Weinberg, adding that a variety of cancer-associated traits once ascribed to tumor cell populations as a whole are now known to be associated with one or another subpopulations of CSCs. CSCs exist side-by-side with normal self-renewing stem cells (SCs); but unlike SCs, CSCs have greatly enhanced tumor-initiating potential thus the ability to seed new cancers.
One critical role of CSCs in metastasis is obvious, Weinberg notes; they act as founder cells, spawning vast numbers of descendants. Indeed, the very traits that define CSCs – self-renewal and tumor initiating ability – also define successful metastasis. However CSCs have other less well-recognized attributes necessary for metastasis: motility, invasiveness, and a heightened resistance to apoptosis. This implies that a multifaceted biological program exists within a primary tumor empowering some cancer cells to escape and start colonies elsewhere. It also suggests that cancer is a systemic disease long before any of the malignant cells begin migrating.
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