How a Tumor Is Like an Embryo
Thirty years ago, cancer was a black box. Researchers knew what went wrong in the body, but not how or why. The work of Robert Weinberg, professor of biology at MIT and a founding member of the Whitehead Institute for Biomedical Research, has helped researchers open that box. Weinberg discovered the first cancer-causing gene and the first tumor-suppressing gene in the early 1980s. Since then, hundreds of such genes have been discovered, and this “treasure trove,” as Weinberg calls it, has led to many new drugs. Weinberg is also helping make sense of a vast amount of complex genetic information by finding global regulators of processes common to all cancers.
Technology Review talked with Weinberg about his research into one of these basic processes. Metastasis–the spread of cancer from its initial site to other places throughout the body–is responsible for 90 percent of cancer deaths. Weinberg suggests that preventive steps, such as taking vitamins, will be key to reducing cancer deaths.
Technology Review: How does metastasis work, and how are cancer stem cells involved?
Robert Weinberg: Until recently, most people–certainly myself–believed that all the cancer cells within a tumor were essentially equivalent to each other. But over the last three or four years, there’s come increasing evidence that within solid tumors, as well as blood-born tumors, there is a hierarchy of cancer cells, with some cells being more important than others. A cancer stem cell is defined as a cell that, when plucked out of the tumor and introduced into a new host like a mouse, is able to spawn an entirely new tumor.
Robert Weinberg describes his research.
Cancer cells initially invade locally in the nearby tissue. Some cancer cells are able to invade into the circulation. They are then carried to distant sites within the body, [escape from circulation,] and invade into adjacent tissue. There they are able to survive and form what’s called a micro-metastasis, which represents a tiny little colony of cancer cells which more often than not fails to develop into a tumor for a variety of reasons, not all of which we understand. On rare occasion, one of those disseminated micro-metastases may indeed figure out a way of growing into a macroscopic metastasis, and as such, it may for the first time create a life-threatening growth.
TR: What is it that allows these cells to form new tumors?
RW: It’s now increasingly apparent that one mechanism, quite possibly the dominant mechanism, involves the ability by the cancer cell to resurrect early embryonic behavioral programs. [In the embryo, these programs] normally enable different tissues to form and depend on the ability of embryonic cells to move from one site in the body to another. This movement in the embryo is superficially similar to metastasis. The way cancer cells acquire this embryonic trait of being able to move throughout the organism depends on their ability to resurrect these early embryonic behavioral programs, which they do through their ability to induce the expression of early embryonic transcription factors [proteins that control the expression of a large number of genes]. In this case, these transcription factors control groups of genes that, when turned on, allow the cancer cells to move, to become invasive, to resist programmed cell death (which otherwise threatens their existence once they leave the primary tumor), and even to release degradative enzymes that break down the [surrounding tissue that] represents an impediment to the forward march of the cancer cells.
TR: If cancer cells are similar to normal embryonic cells, is it surprising that we don’t get cancer more often or earlier?
RW: It says, rather, that cancer cells are not as clever as we think they are. Rather than having to cobble together complex behavioral problems, they simply resort opportunistically to resurrecting behaviors which are normally suppressed in adult tissue, and therefore do not represent an imminent threat to the organism because they’re kept under tight control. (There are multiple mechanisms implanted in our cells and tissues that impede the formation of tumors.)
This scenario I’ve just depicted is very heartening for us because if one looks at the biology of metastatic cells, it seems to be so complex as to be bewildering beyond anyone’s ability to understand it, simply because there are so many different genes and proteins involved. However, if one is now able to trace these behaviors to a small number of central regulators, each of which can act by modulating the expression of a whole cohort of responder genes, now one has greatly simplified the problem, because now one can focus one’s attentions on two or three distinct central regulators that choreograph the traits of high-grade malignancy.
TR: How has our understanding of cancer changed during your career?
RW: In the mid 1970s, we knew nothing about why cancer cells misbehaved. We knew they did misbehave, but they were a black box. Over the next quarter century, there was an enormous avalanche of information that came out that described the fact that many but perhaps not all the traits of cancer cells and tumors could be ascribed to damaged genes that reside within the cancer cells. Prior to 1975, that was a total speculation. So there’s been a radical about-face in terms of that. Now cancer is no longer a mystery in terms of how it arises.
TR: What big questions remain?
RW: What we still don’t really understand is why certain people get cancer and other people don’t. We understand that people get lung cancer because they smoke. But we don’t really understand why they get breast or prostate cancer–yet. But I think that will emerge with increasing clarity over the next decade. Still, we know quite a bit about why breast-cancer cells misbehave, while at the same time being able to point to the causative factors of lifestyle and family history that dictate their susceptibility to developing the disease.
TR: When is there going to be a cure for cancer?
RW: If you look at the death rates for cancer in this country, they’ve been going down for most but not all kinds of cancer. There’s not going to be a single, dramatic cure. Instead, there will be a series of cures that will be developed over the years that will progressively lower the death rate. It’s going to be incremental gains. There may be certain dramatic battles that are won–certain kinds of cancers will be converted from a life-threatening to a chronic disease.
In the long run, the biggest reductions in cancer mortality will actually come from prevention, not treatment. So one can probably halve, maybe even decrease by two-thirds, one’s risk of getting cancer by not smoking, by not living with smokers, by staying slim, by having a diet which is high in vegetables and low in red meats, by getting exercise, and maybe in the future by taking different kinds of vitamins. It’s still a little bit sketchy as to which ones. The risk of dying from cancer, which is now about one in five, may go down to one in ten, or one in fifteen. Could be.
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