Thought high school was bad? Check out the peer pressure of cancer cells.

Kyle M. Loh May 7, 2010 0

When Anakin Skywalker turns to the Dark Side of the Force, who's responsible? Granted, Padawan Skywalker is not the sharpest tool in the shed, and has his fair share of teenage emotional problems (dreaming that his wife is dying, randomly killing people, etc…), but Darth Sidious (Emperor Palpatine) — the manipulative old man with the creepy face and glowing eyes — was probably the cause of all of it. When Anakin Skywalker fell to the Dark Side, it was mostly Darth Sidious's fault — not his fault. 

 

Given that we just made a scientific hypothesis based on Star Wars, it is then unanticipated that many biologists cling onto the notion that when normal cells "go bad" and transform into cancer cells, that it's the cell's own fault for becoming cancerous — not the cancer cell's friends (that is, the creepy Sith cells right next door).

 

 

Countless studies have been done by cancer biologists to examine the various internal events that make a cell turn into a cancer cell. For example, it is known that sources of DNA damage (such as UV radiation, reactive oxygen species, etc…) directly damage a cell's genome, leading to mutations in the genome and thus "breaking" many genes and making them nonfunctional or giving them mutant activities. The mutation and inactivation of various tumor suppressor genes turns cells into cancer cells, and indeed, recent genome-wide studies of human tumors have shown that many tumors carry mutations in tumor suppressor genes such as p53, Rb, and PTEN. Mutations in these tumor suppressors in cancer cells are so prevalent that it is strongly believed that mutation and "breakage" of these tumor suppressors is a necessary event in order to corrupt a normal cell into a cancer cell.

While massive numbers of outstanding studies have examined the internal mutations and signaling events that turn a normal cell into a cancer cell, relatively few studies have examined the external influences that can convince a cell to become cancerous — that is, the "peer pressure" exerted by neighboring cells that encourage the cell to become a cancer cell.

When one thinks about it, this hypothesis really revolutionizes our perspective on cancer. It is natural — and logical — to look for "what does wrong" in a cell to make it cancerous. It's really a very different dimension to consider that the cell might not walk the cancerous road just by themselves, and that neighboring cells are deadly participants in encouraging cancer. Thus, we have established two complimentary, elegant hypotheses on tumorigenesis: one that suggests that internal events within a cell can make it cancerous, and another that suggests that neighboring cells can signal to a cell and help encourage its cancerous progression. This not only opens a much wider view of cancer and tumorigenesis, but as the clinician immediately thinks, it opens a whole new world for novel cancer therapeutics — ones that don't target the cancer cell directly but instead target the cancer cell's bad friends that are encouraging it to hate the world and wreak mayhem. 

In this "peer pressure" hypothesis, the bad influences come from a cell's "niche" — its microenvironment in the body. It's easy to forget when studying cells in a dish that in the body, they are surrounded by numerous neighboring cells of different types, extracellular matrix, and systemic fluids. In the body, a very complex 3D structural environment helps instruct a given cell's behavior, and numerous extracellular signals from nearby and faraway cells can potentially drastically regulate a cell's behavior as well. 

A recent study published in Nature by David Scadden (Co-Director of the Harvard Stem Cell Institute) has examined this concept that a cell's niche can instruct it to become cancerous. They focused on bone — which is bone marrow surrounding some hematopoietic stem cells (the cells responsible for making your blood; that's why bones on the inside appear red). So, in the hematopoietic niche, hematopoietic stem cells are surrounded by bone marrow niche cells. The paper showed that manipulation of bone marrow cells (by inhibiting microRNA production) surprisingly led the hematopoietic stem cells to become cancerous. Manipulation of the bone marrow doesn't make it cancerous — instead, it makes the nearby hematopoietic stem cells to become cancerous.

Another paper in Nature written by Lee Rubin (my former collaborator at the Harvard Stem Cell Institute) showed that surprisingly, an anticancer drug (Hedgehog inhibitor) doesn't kill cancer cells when directly applied to them — this is initially extremely surprising. Instead, the paper very elegantly showed that human pancreatic and colon cancer cells need "peer pressure" from nearby niche cells to continue spreading. Addition of this anticancer drug to the surrounding niche cells stops them from feeding these bad signals to the cancer cells, leading to the remission of the tumor. 

Likewise, two papers in Cell also show that mutations in two cancer genes (Rb and RARy) don't actually directly induce cancer in normal cells — instead, it is only when these genes are mutated in niche cells that cancers are initiated when these niche cells carrying these genetic mutations begin to exert "peer pressure" on cells to make them cancerous.

Altogether, we paint a very interesting idea of the social lives of normal cells and cancer cells. We've known for a long time that people "go bad" often partly by themselves and partly because of their bad friends. Here, we extend the same observation to cancer cells — that they are fueled by their own internal corruption as well as the negative "peer pressure" exerted by neighboring niche cells. Hopefully, this hypothesis will help design novel, orthogonal cancer therapies that will not only target the cancer cells themselves but also their bad friends.

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