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Most likely…to metastasize
Once a polyp has developed – and if it is not removed – that polyp will likely develop into a carcinoma, a malignant tumor of the epithelium, with the potential to spread.
This transition – from a benign polyp to malignant cancer – is often associated with mutations in the p53 gene, another tumor suppressor. The protein it encodes has many nicknames – “guardian of the genome,” “the guardian angel gene,” and the “master watchman” – reflecting its importance in preventing potentially cancer-causing mutations.
About 50 percent of colon cancers have a mutation in p53, which causes the protein to lose its cancer-fighting function.
“If you lose p53, you lose the ability of the cell to undergo programmed cell death in response to DNA damage. So these cells don’t commit ‘suicide’ when they’re supposed to,” says Beauchamp.
“It’s not clear that loss of p53 is the event that tips these tumors into becoming invasive carcinomas, but it certainly contributes in some of them.”
The genetic alterations that propel cancer cells to invade and metastasize to distant tissues – the aspect of cancer that causes most cancer deaths – remain perhaps the biggest question in cancer biology.
The process requires that the tumor cells, which are at first sequestered in their tissue of origin, to break free of the molecular bonds that hold them there. One class of bond-forming proteins
is the cadherins. Cadherins reside on the surface of cells, and E-cadherin (the “E” is for “epithelial”) molecules on adjacent cells “zipper up” and bind those cells together while maintaining normal polarity. Loss of E-cadherin function seems to be a required for a cancer to become invasive.
Beauchamp is currently leading a screen for compounds that restore E-cadherin function, in hopes of finding ways to reverse the epithelial-mesenchymal transition that contributes to metastasis.
“In epithelial cells, loss of E-cadherin or E-cadherin function marks the transition to metastasis,” explains Albert Reynolds, Ph.D., a professor of Cancer Biology at Vanderbilt. “Before that happens, you can just take the tumor out and people are fine. After that, it’s pretty rough going.”
About 20 years ago, Reynolds discovered a partner of E-
cadherin, a protein called p120-catenin, a molecular “cousin”
to beta-catenin. The protein binds to the tail of the E-cadherin
protein, which dangles into the interior of the cell, and regulates cadherin function.
His lab recently showed that p120’s role is much broader
than simply regulating cadherin function. They found that p120 is actually at the nexus of several different signaling systems involved in cancer progression.
“p120 is central, not only to cadherin signaling, but to crosstalk between different systems in the cell that regulate motility, cell-cell adhesion, and growth,” Reynolds says.
Reynolds and colleagues are now working on mouse models to evaluate the effects of p120 loss in colon and breast cancers. While clinical application of the findings are yet to be realized, Reynolds predicts that drugs that target p120, or other components of this complex pathway, could be useful inhibitors of metastasis. In fact, says Reynolds, “everything about the cadherin complex has been implicated in cancer.”
Reply hazy…
While we now know a lot about the genetic alterations involved in colon cancer, a vast frontier remains unexplored.
For example, researchers are fairly certain that cancer usually starts in one cell. But what cell? And where is this cell located within the colonic crypt?
Mature epithelial cells reside at the “peaks” of the colonic crypts, while proposed stem cells are tucked away at the base of
the deep “valleys” of the crypts.
If the cancer’s origin is in the colon epithelium, which cell is
it that accumulates the cancer-causing mutations? Are the ever-
elusive “stem cells” the source?
“There’s a controversy in the field,” Coffey explains. “Does colon cancer go top-down (from mature epithelium to stem cells) or bottom-up?”
While some cancer biologists think it proceeds top-down with the initiating event in the mature epithelial cells, Coffey thinks that it is more likely that colon cancer starts at the bottom – in
the stem cells sequestered at the base of the colonic crypts.
Using genetically engineered mice and techniques that can alter the expression of cancer-promoting genes in specific parts of the colonic crypt, Coffey hopes to answer that question.
“It is such a fundamentally important biological question,” he says, “but nobody has done this yet …because nobody has had the tools to do it.”
Now Coffey thinks it is possible to find the exact cells in which colon cancer originates. This information could usher in a new way of thinking about colon cancer development and therapy.
Additionally, non-epithelial cells may be an overlooked
contributor. But Hal Moses, M.D., Vanderbilt-Ingram’s founding director, and colleagues have shown in mice that disrupting
TGF-β signaling in the surrounding, supportive cells – called
stromal cells – can initiate a cancer in the adjacent epithelium of the prostate and forestomach. The findings highlight the importance of the tumor “microenvironment,” an aspect that remains a major area of exploration for Vanderbilt-Ingram researchers.
For now, the best defense against this disease is screening
and early detection. The current recommended age for having a
screening colonoscopy is 50. If a patient has a family history of colon cancer or symptoms suggestive of polyps or cancer, a screening colonoscopy should be done earlier.
Although it is the best we have, Beauchamp knows that even strict compliance with colonoscopy screening recommendations may not catch everyone, especially those who are young and asymptomatic.
Patients must be proactive and advocate for themselves, he says. Tell your doctor if you’re experiencing symptoms and – especially if you experience bleeding – ask for a colonoscopy if one is not offered.
“Anybody who has rectal bleeding has to be worked up for the possibility of colorectal cancer. Odds are they won’t have it, but you can’t tell…until you actually check.” 
More information about Vanderbilt-Ingram’s gastrointestinal cancer research at: www.vicc.org/research/programs/gi.php
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