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APC is just a part of a much larger system, called the Wnt
signaling pathway. The pathway is activated during the development of the early embryo, and it is highly regulated in adult cells. However in many cancers – colon cancer especially – this embryonic pathway becomes dysregulated, most often by mutations in APC.
“When you lose functional APC, one of the consequences is that you activate the Wnt pathway,” explains Coffey. When the pathway is activated, another molecular component of the pathway, called beta-catenin, is freed from the cell surface to go into the cell’s nucleus. There, he says, “it will turn on genes that we think are critically important in the development of colon cancer.”
So, even if a person has two normal copies of APC, mutations in other steps of this pathway – in beta-catenin, for example – can also activate the pathway, producing the same cancer-promoting effect. Vanderbilt developmental biologist Ethan Lee, M.D., Ph.D., has found that another pathway component, called Axin,
is a central regulator of Wnt pathway activity.
Based on a mathematical model, “we can propose that controlling Axin levels and its turnover is the major way by which this pathway can be regulated,” says Lee, an assistant professor of Cell and Developmental Biology.
Using a test tube-based assay Lee developed to study Wnt
signaling, his team has identified several compounds that inhibit the pathway.
“The idea is that if any of these compounds work out, they can be potential tools to study the pathway and – further down the line – as potential drugs.”
One of these, called VU-WS30, is showing promise: it inhibits the growth and viability of cultured cancer cells. Lee found that it works by inhibiting Axin degradation and stimulating beta-catenin degradation – pathway alterations that inhibit cell growth.
It’s an exciting lead, says Coffey. “If you lose APC…but you make enough Axin…you can compensate for the loss of APC.” And because the drug is already an FDA-approved compound (for diseases other than cancer), that would accelerate the process of testing it as an anti-cancer agent in humans.
Signs point to… progression
While APC mutations and other mutations that activate Wnt signaling are necessary for the development of early polyps, the progression onward to colon cancer requires additional genetic alterations.
“Even though most cancers are initiated that way (by activations of the Wnt pathway), that doesn’t fully explain the behaviors of all cancers,” says Beauchamp. “It gets the ball rolling, but you can still have a wide diversity of tumor behavior downstream of that initiating event.”
Mutations in a gene called K-ras are associated with the progression from small polyp to large polyp. K-ras is an oncogene – a gene whose protein product promotes cell growth and division – and about 40 percent of all colon cancers have mutations that activate or “turn on” K-ras function when it shouldn’t be on, Beauchamp notes.
Like APC, K-ras is just one link in another chain of cell signaling molecules, called the MAP kinase pathway. This pathway also includes a protein called B-raf, and mutations in the gene encoding B-raf have also been identified in colorectal cancer.
A certain proportion of cancers – about half – will have a defect in a growth factor pathway called the TGF-β (transforming growth factor beta) signaling pathway. In one type of hereditary colon cancer (called HNPCC, or hereditary nonpolyposis colorectal cancer), about 90 percent of patients have a loss of one piece of this pathway – the TGF-β type II receptor.
Still other tumors may have mutations in other components of the TGF-β pathway, called Smad proteins. Beauchamp is examining the roles of TGF-β and the Smad proteins in the process of epithelial-mesenchymal transition – a reversion of cell behavior to a more embryonic state. This process is thought to be a critical – and potentially reversible – step in cancer progression.
Another growth factor, called EGF or epidermal growth factor, also seems to have an important role in this “establishment” phase of colon cancer.
Coffey and colleagues have shown that, in mice that carry the initiating mutation in APC, reducing EGF receptor signaling decreases the number of adenomas (polyps) by 90 percent.
So for a small polyp to progress, “it’s very important to have intact EGF receptor signaling,” Coffey says. And several targeted cancer therapies – Erbitux (cetuximab), Tarceva (erlotinib) and Iressa (gefitinib) – now exploit and try to inhibit EGF receptor
signaling to stall the progression of cancer.
But these later genetic events occur in only certain fractions
of tumors, says Beauchamp. So while knowing which of these mutations a patient has might not predict whether they develop cancer initially, these genetic signposts may be particularly useful in determining prognosis and predicting response to treatment.
For example, “patients with activated MAP kinase pathway – like those who have mutations in K-ras or B-raf – are unlikely to respond to therapies targeting the EGF receptor,” he says.
Recently, Beauchamp’s lab has identified a set of genes that seem to predict a poorer prognosis in colon cancer. This may eventually help clinicians choose the appropriate course of action for patients based on the gene expression “signatures” found in their tumors.
While these mutations are not currently tested for as a part
of standard cancer care, identifying these genetic signatures could help predict which tumors are most likely to progress, which patients are at highest risk of recurrence and metastasis, and which patients will respond to particular therapies.
“Ultimately, this will lead to more individualized therapy for cancer patients,” says Beauchamp.
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