Emerging insights into cancer

The adult human body contains approximately a hundred trillion cells, a majority of which are post-mitotic (i.e. incapable of self-replication). The inappropriate and uncontrolled proliferation of such post-mitotic cells results in cancer (at least that’s what we’ve known/thought for a while now). Anyway, the transformation of normal differentiated cells is not a simple event/process, because the body has its checks and balances. For a normal cell to turn cancerous, it would have to acquire the hallmarks of cancer, i.e. obtain and sustain proliferation signals, acquire limitless proliferative capacity, circumvent the apoptotic (programmed-cell-death) pathway, elude the immune system and, finally, acquire the capacity to invade tissues and metastasize. Therefore cancer has historically been thought to result from a multi-step process involving the progressive accumulation of damage to post-mitotic cells that eventually leads to their neoplastic transformation.

Over the past couple of years however, a different aspect of cancer has begun to emerge---one that is connected to the basic biological process of cell replenishment. The human body sheds (and replenishes) billions of cells each day. One simple way to replenish these cells would simply be to replicate differentiated cells of the appropriate type (so, to replace shed skin cells the body could just replicate some already-differentiated skin cells in the area) to make up the deficit. But that is not what happens. In reality, cell-replenishment involves a more laborious, energy-intensive process wherein the requisite cells are ‘made from scratch’ each time. This is achieved by drawing on populations of adult pluripotent stem cells and stimulating them to proliferate and differentiate into the required cell types.

What advantage could such a strategy confer on the system? A very important one actually, as it could reduce the chances of somatic evolution. What does that mean? Well, differentiated cells and tissues have already gone through a number of cell divisions and developmental programming----and have probably acquired damage/mutations over time. Proliferation of such differentiated cells would create the risk of propagating deleterious mutations and abnormal cells, some of which could be cancerous. So, by going back to adult stem cell pools for cell replenishment, the body essentially goes back to a ‘clean’ genetic lineage and reduces the chances of propagating aberrant cells.

Here’s where it gets interesting with respect to cancer. A significant implication of the aforementioned strategy is that the genes that regulate patterning and differentiation in our body are not just required during embryonic development. Rather, it is likely that most of these genes also function on a daily basis to direct the differentiation of adult stem cells into myriad cell-types for cell replenishment. What can happen then, if an adult stem cell acquires a mutation that disrupts any of these differentiation programs? Well, one would predict that this could result in the generation of rogue stem cells that, when stimulated to differentiate, may fail to check their proliferation at the appropriate time after differentiation. Remember, these cells are already endowed with the capacity to proliferate, spread and invade tissues (as they are required to do during normal cell replenishment); therefore a single error that disrupts the differentiation program can be sufficient to render these stem cells cancerous. This concept of cancer stem cells is now very hot in cancer research. For one thing, the presence of cancer stem cells may hold the simplest explanation for why many cancers reappear after treatment. [Surgical removal of tumors or chemical/radiological elimination of (rapidly dividing) cancer cells will likely not be able to harm the (slowly dividing) mutant stem cell population. And the next time a mutant stem cell contributes to cell replenishment, the cancer will naturally reappear].

But what is even more interesting about this recently uncovered aspect of cancer is that it invokes a paradigm shift in thinking on the origins of (and possible future therapies for) cancer. Cancer need not only be the result of multiple events in post-mitotic cells. A single mutation in an adult stem cell could cause it. Furthermore, that mutation could very well be in a gene that regulates patterning or differentiation.

A corollary of this paradigm-shift is that cancer research is no longer limited to the signaling police, cell-cycling enthusiasts and the undertakers of apoptosis research. Rather, it has now also clearly entered the realm of differentiation and the evolution of developmental systems. Man, is there nothing evo-devo cannot tackle? Evo-devo would now like a vodka martini, shaken not stirred.

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