"Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer"
http://www.ncbi.nlm.nih.gov/pubmed/26091037
I don't write this blog for colon cancer specialists, researchers or graduate students, but to more general audience in mind. So, following is a little bit of background.
There is a human genetic disease called Familial Ademonatous Polyposis, that produces numerous polyps and cancers in colon. A mutation in a gene called APC is the cause of the disease.
Apc mutations occur in 80-90% of human colon cancers, so Apc is considered a major tumor suppressor in colon cancer. In fact, apc protein interacts with over 100 other proteins and works as a major signaling hub in colon. So it makes sense if apc mutation can cause wreck havoc in the tissue regulations.
We knew transgenic apc mice develop intestinal polyps, and have used transgenic apc mice model to test/develop colon cancer prevention/therapy drugs for decades.
This paper uses new transgenic apc mice model (in which they can shut off/turn on apc expression in intestine with induction drug treatment) to prove that (i) apc shut-off leads to tissue dysplasia and intestinal cancer development, and (ii) apc turn-on led to re-differentiation of cancer and can restore normal intestinal tissues. (iii) They also tested to combine other mutations known to facilitate intestinal cancer development (i.e. p53 and k-ras). The double mutations led to more aggressive cancer development, but re-expressing apc could reverse the cancers as well.
There are more details interesting to us, but I'll save the details. This paper was published in journal Cell, which is considered as one of the most prestigious journals. So researchers in other field tend to treat papers in the journal with respect, and researchers in the same field reads them seriously.
My impression was, "wow. that sounds too good to be true. What happened to current paradigm that cancer develop after acquiring many, like 20+ mutations? Can Apc restoration alone reverse them?"
Their conclusions suggest that reestablishing normal-functioning apc may be able to reverse cancers (with a reservation that their model probably do not reflect more advanced, stage 4 cancers that are most problematic clinically). Although restoring apc in actual cancer without genetic tricks may be difficult in practice, the drastic effect of apc restoration was certainly impressive.
[Intestinal tissue dysplasia, adenoma and adenocarcinoma due to apc loss (and k-ras or p53mutation) can be reversed by reintroducing apc]
I write about this paper in this blog because of simplicity of their results, and of some thought-provoking aspects. For a few days, I find myself thinking about the results, trying to digest them and put them in place.
Their cancer development model is along the line with contemporary cancer stem cell model. Apc loss can turn cells to somewhat stem cell-like cells, so they acquire ability to multiply outside of normal, differentiated state. The change is a strong driving force to form cancers.
There are many functions in the body that can work against cancer development, such as immune surveillance, cell death, differentiation and senescence. Their apc-loss model can override all these other factors, or so it seems. I wonder how the other "brakes" can (or cannot) be augmented to suppress cancers as well.
