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Interesting article about metatases

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http://www.nytimes.com/2007/04/03/healt ... .html?8dpc

A Mutinous Group of Cells on a Greedy, Destructive Path

However much their politics and personal styles may otherwise divide them, Elizabeth Edwards and Tony Snow have now been linked in the public eye by a brutal disease that itself flouts the body’s partitions and ruptures the compartmentalized calm of which we all are built.

In quick, sad succession over the last two weeks, Mrs. Edwards, the 57-year-old wife of the presidential candidate John Edwards, and Mr. Snow, the 51-year-old press secretary to President Bush, announced that the cancers for which they had previously been treated had returned and metastasized: in her case, spreading from breast to bone, in his, from colon to liver. Both vowed to fight their resurgent disease, and given the possible treatments now available, they could well have years more of productive, if sometimes rough-edged, life before them. When Katie Couric said in a “60 Minutes” interview with Mrs. Edwards how hard it must be “staring at possible death,” Mrs. Edwards correctly shot back, “Aren’t we all, though?”

Yet in truth, metastatic cancer remains one of the grimmest conditions a person can face. Patients rarely die from the effects of a primary tumor; 90 percent of deaths from cancer are the result of metastases, of malignant cellular outposts proliferating far from the neoplastic mass that spawned them. They are barbarians, the colonist cells, co-opting all nutrients in their adopted organ and starving their normal neighbors of air, sugar and salts, and blocking traffic and clogging conduits, and finally, when their greed exceeds their easy grab, tearing open surrounding cells and feasting like cannibals on the meat of their fellows.

This, of course, is outrageous. We are each of us an obligately multicellular community, in which many trillions of microscopic cells have joined forces and fates, have specialized in the tasks to which they were assigned during our embryonic development. You over there, in the neural crest, you will be a melanocyte and help pigment a freckle. And you, in the midline ridge of the limb bud, you will be a bone cell of an index finger that will someday point firmly at a reporter’s raised hand. With all the normal cell divisions that occur throughout life, the chronic replacement of skin, hair and intestinal lining, the constant remodeling of our bones and retooling of our immune system, we go through about 10 million billion cells over our four-scorish span. The vast majority of those cells behave and do their job, as though innately aware that only the gametes can jump ship and live to tell about it. So what gives with metastases? What turns them into such oblivious, self-important, suicidal fools?

Biologists know quite a bit about the steps that transform a normal cell into a cancer cell, a cell that lawlessly divides and gives rise to a primary tumor. They have identified genetic mutations and chromosomal aberrations that prompt cells to think they are being stimulated by growth hormones when they are not, that stifle safety signals meant to keep cell division in check, and that shore up the tips of chromosomes and so immortalize cells that otherwise would be slated to die. Researchers’ grasp of metastasis, by contrast, remains relatively sketchy, one reason being that whereas the initial stages of malignant transformation can be analyzed in vitro, in the controlled setting of cultured cells, metastasis — which is Greek for “beyond static” — is a matter of cells on the move and ultimately must be studied in vivo, in the bewildering wilderness of the body.

Nevertheless, researchers have some clues. They have learned that full-blown metastasis is an extremely challenging trade, and that the great majority of cancer cells are not up to the task. Even those malignant characters that manage to slither their way into the blood or lymph system usually fail to do anything further. In his newly published book, “The Biology of Cancer” (Garland Science), Dr. Robert A. Weinberg of the Whitehead Institute in Cambridge, Mass., points out that in experiments with mice carrying bulky tumors of a billion cells each, perhaps a million cancer cells are seeded into the rodents’ circulation each day, “yet the visible metastases formed in such animals may be counted on the fingers of one hand.”

The body’s transportation networks are fraught with danger to unlicensed migrants, and not just from the body’s defense system. Because most tumor cells lack the streamlined form of the blood and immune cells that are designed for cross-body trafficking, shear forces in the smaller vessels may rip the intruders apart.

To survive the journey, malignant cells must reinvent themselves as parasites. A few manage to slim down to almost bacterial dimensions by pinching off unnecessary hanks of their cytoplasm. Others take on what Dr. Weinberg calls “hitchhikers,” attracting an entourage of platelets and red blood cells to their surface “to escort them through the rapids into safe pools within tissues.”

Such oases might be wound sites to which the chaperone platelets handily stick, enabling their companion cancer cells to gain their first toehold in virgin terrain — and to begin feeding on the rich broth of growth hormones and factors with which wound sites typically teem. In one 1993 report, Israeli oral surgeons described 55 cases of dental extractions in which the procedure was followed days to months afterward by the eruption of an ugly metastasis where the tooth had once been; for a third of the patients, the appearance of the gumline growth was the first sign that an internal organ was riddled with cancer.

Yet even after malignant cells have settled onto a new site, their replicative success is hardly guaranteed. Most appear to either die or lapse into dormancy. Patients may harbor thousands or millions of these dormant micrometastases without suffering a fatal relapse of the disease. Evidence suggests that micrometastases will not attain macro dimensions unless, among other things, they adapt to their new surroundings and interact with their neighbors enough to exploit them. This helps explain why different types of primary tumors tend to metastasize to their “preferred” organ: cells learn a skill set from their tissue of origin, and some lessons are more easily applied to one novel setting than to another. Breast tumors, for example, are known to metastasize to bone tissue, where the invasive cells perversely take advantage of their ability to gather calcium ions for breast milk and apply it to the rampant dissolution of calcium-rich bone. Malignant melanoma spreads readily to the brain, presumably because neural tissue and the melanocytes that give rise to melanoma both arise from the same class of cells during gestation.

Cancer may be short-sighted, but it is life stripped raw and caterwauling, life determined to divide at all costs, and to go back to the womb, and to be born all over again.

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