The Moriarty of Cancer: Cancer Stem Cells At A Glimpse

But in calling Moriarty a criminal you are uttering libel in the eyes of the law—and there lie the glory and the wonder of it! The greatest schemer of all time, the organizer of every devilry, the controlling brain of the underworld, a brain which might have made or marred the destiny of nations—that’s the man! But so aloof is he from general suspicion, so immune from criticism, so admirable in his management and self-effacement, that for those very words that you have uttered he could hale you to a court and emerge with your year’s pension as a solatium for his wounded character.

Sherlock Holmes, The Valley of Fear – A.C. Doyle (1915).

Edited by Navjot Kaur

As rules of thumb go, there is probably none which biologists are so resigned to, as that life never ceases to bamboozle. If there exists a highly efficient, amazingly complex process in one organism, rest assured, an even more ridiculously intricate one will crop up in another.

It’s along these lines that we cross paths with our adversary of the day – the cancer stem cell (CSCs). But first, onto its more mainstream, vanilla version – the Stem Cells.

Stem cells certainly do live up to their names – they are indeed the “stems” from which cellular diversity arises. Essentially, a stem cell is a sort of forefather which can divide into daughter cells that are highly specialized for different types of specific functions. This specialization process is called differentiation, wherein cells take up distinct roles that help form and demarcate the different systems in our body. The progenitor stem cells can hence divide as per requirements to supply daughter cells with dedicated roles.

These stem cells are particularly important when we consider how an organism’s body repairs itself, or even how an embryo develops into a full-fledged organism. In the former case, loss due to injury, disease, or regular maintenance/replacement of older tissue is based on the ability of these stem cells to divide and provide all the other required cell types. A more dramatic demonstration is seen in the case of embryo development – starting from just a single cell, through divisions and differentiations, these stem cells can take part in complex processes to generate the dazzling diversity of different cells we see in an adult organism.

Clearly, we have on hand a miraculous ability indeed! Over the years, we have gained the capabilities to grow and study these stem cells in laboratory settings. Quite understandably, they have now become the focus of extensive research and clinical applications, ranging from regenerative medicine to cancer treatment. These cellular marvels are undeniably the wily puppet-masters of an organism’s life.

Except, when the strings of fate turn black – courtesy the CSCs.

The CSC is, beyond question, a remarkable entity. At its most basic, it’s but a cancer cell with stem-like properties. It divides relentlessly, and can maintain (or one may say, protect) its own stem-like state with impunity against the body’s regulatory mechanisms. Thereby, it ends up serving almost as a factory for the production of new tumor cells – leading to aggressive tumor growth. Not only that, the CSCs are powerful stimulants which facilitate tumor progression using multi-faceted strategies.

In any body, the appearance of a tumor is cause enough for alarm bells to be set off. The ever-dependable immune system is reigned in, and the body undertakes measures to eliminate what it perceives as unnecessary baggage. But woe betide one, for the CSCs are lurking – ever ready to thwart these attempts by our body to restore normalcy. They actively suppress the functions of the body’s immune cells, and even go so far as to actually recruit and convert them into aiding tumor growth.

And you thought enemy units could only be converted by the monks in Age of Empires?

Infact, one may even quote Holmes on Moriarty to accurately surmise this:

For years past I have continually been conscious of some power behind the malefactor, some deep organizing power which forever stands in the way of the law, and throws its shield over the wrong-doer

Sherlock Holmes, The Final Problem – A.C. Doyle (1893)

Lesser and lesser of a coincidence, eh?

A flowchart made by my friend Kallol Mozumdar for a paper Bhushan and myself co-authored in 2017. Technicalities aside, the image conveys an idea about the unbelievably intricate pathways the CSC adopts to survive and adapt within the body, in conjunction with an array of different cell/tissue types, as well as physical environments. The interaction is highly dynamic, and essentially mutual in nature. Arrows labelled “A” indicate the effect exerted by the CSCs on various elements, whereas “B” indicate the consequent benefits/effects on the CSCs.

And just like Moriarty isolated himself from the reaches of the law, the CSCs don’t lag behind either. Adept at carving out cozy, well-protected niches for themselves, they can often cause the rearrangement of extracellular fibers to form physical barriers shielding them from chemotherapeutic drugs. Other studies have demonstrated eye-brow raising effects – CSCs may actively recruit regular, non-cancerous cells of your body to help remodel the environment around tumors into a more favorable setup for the CSCs themselves. As they maintain themselves in these well-sheltered, interior regions of tumors, it is often very difficult to target them using conventional methods. Truly, as Holmes said:

He sits motionless, like a spider in the center of its web, but that web has a thousand radiations, and he knows well every quiver of each of them. He does little himself. He only plans. But his agents are numerous and splendidly organized.”

Sherlock Holmes, The Final Problem – A.C. Doyle (1893)

The incredible scope of a CSC’s effect on nurturing and directing tumor growth is by no means limited to these instances. They can significantly enhance a tumor’s resistance to chemotherapeutic drugs, and are ridiculously stubborn to kill off using therapy due to their own high-resistance adaptations. This is one of the major reasons why most cases of cancers recurring even after prolonged treatment is attributed to them having escaped the initial purge and staying alive unharmed long enough to instigate a second, more violent uprising. 

Such devious plotting, and such terrifyingly clever machinations! CSCs truly represent a stunning example of Nature at its scheming, destructive best.

And no wonder they’re now the focus of extensive biomedical research aimed at unlocking their very many secrets. How, for instance, does a CSC “convert” and “recruit” the body’s own, un-diseased cells? Could we inhibit this signaling – which could, of course, be a powerful weapon to target these cancer cells? Or how do they so effectively maintain and retain their stem-like nature? What are the steps leading upto the evolution of CSCs in the first place?

These are extremely pertinent questions, which will have staggeringly impactful answers, if and when discovered. An understanding of these core processes could hold the key for designing powerful new treatment strategies which may help us gain a strategic edge in the now more than a century old war on cancer. Hopefully, just like good ol’ Sherlock, we might just be able to gain the upper hand, and send CSCs spiraling down into oblivion.

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