Unchecked cell growth is the essence of cancer, so much basic research has focused on how cancer cells escape normal growth controls. Scientists have turned their focus to a family of secreted growth regulatory proteins, known collectively as transforming growth factor-beta (TGF-beta), which are one of the few known classes of proteins that can inhibit cell growth.
First identified in 1978, the TGF-beta system is now known to be highly conserved throughout the animal kingdom, and its basic pathway provides a simple route for signals to pass from the extracellular environment to the nucleus. This process involves TGF-beta I, II and III, which are three different molecules that all activate the same intracellular receptor.
TGF-beta is involved in an extraordinary range of biological processes, including embryonic development, wound healing and angiogenesis. In its normal state, the TGF-beta pathway restricts cell growth, differentiation and cell death.
When a normal cell becomes cancerous, various components of the TGF-beta signaling pathway become mutated, which makes the newly cancerous cell resistant to the effects of normally functioning TGF-beta. These resistant cells then grow without regulation.
Previous research has shown that in colon cancer, one third of tumors have mutated TGF-beta receptors, and the remainder of the tumors have mutations in the signaling pathway activated by TGF-beta, both conditions that lead to unchecked proliferation. Scientists believe that, in general, a higher level of mutated TGF-beta leads to poorer prognosis.
In its normal state, TGF-beta has been shown to decrease the likelihood of cell proliferation, including cancerous cells. So scientists are turning their attention to what causes TGF-beta to mutate.
Recent research in breast cancer suggests that VE-cahedrin enhances the signaling pathway of mutated TGF-beta. VE-cahedrin is a specific cahedrin that plays a central role in vascular barrier function. Cahedrins are adhesive molecules that glue our cells together. Although the research is currently only at the laboratory stage, scientists believe that the combination of increased mutated TGF-beta and VE-cahedrin may increase the risk of malignancy and metastasis.
Other laboratory research has focused on the methylation, or silencing, of genes shown to cause TGF-beta mutations. In one animal study of prostate cancer, researchers identified the Tgfbr2 gene and found its methylation in more than half of prostate cancer cell lines studied. Tgfbr2 plays a key role in the production of TGF-beta and researchers believe its methylation may lead to cancer-causing mutations.
Possible New Therapies
As scientists continue to understand the basic biological mechanisms behind the expression and mutation of TGF-beta, other researchers are performing early trials of drugs that may inhibit the growth of mutated TGF-beta.
The foundation of most of this research is immunology. Laboratory scientists have noted that, in its proper form, TGF-beta has a significant immune response by regulating certain parts of the inflammatory cascade, the production of dendritic cells and natural killer cells. However, when TGF-beta mutates, or is over-activated, it has exactly the opposite effect and instead leads to the promotion of tumor cells. Scientists believe this makes TGF-beta an attractive target for immunotherapy.
Troglitazone, a member of the class of drugs called PPAR (peroxisome proliferator-activated receptor) antagonists was recently tested on laboratory models of glioma. PPAR agonists are mostly used for patients with diabetes, but they also have anti-inflammatory properties. Researchers found that troglitazone was able to suppress mutated TGF-beta and block glioma progression without significant neurologic damage.
Because mutated TGF-beta has also been shown to play a key role in metastasis, scientists tested whether inhibition of TGF-beta with LY2109761, an experimental TGF-beta inhibitor, would have any effect on pancreatic cancer metastasis. In experimental animal models, LY2109761 reduced tumor burden, prolonged survival and reduced spontaneous abdominal metastases.