Why Isn't Cancer More Common?

Epigenetics and Aging (20)

Why Isn’t cancer more common? This is a question Mina Bissell raised (21383745). In her words, “Why don’t we get more cancer?”. This question will strike some as odd, as cancer is such a prodigious scourge. But given the assumptions of the somatic mutation theory of cancer, it is a conundrum. Consider the fact that in each human body there are 30-60 trillion cells, the vast majority of which could potentially initiate carcinogenesis.

Assuming no exposure to environmental carcinogens, somatic mutations will inevitably arise because of errors in DNA repair during cell division. The mutations will be transmitted to each successive generation of cells derived from the initial mutant. And in each subsequent cell division there is a non-zero probability of another mutation. As such, mutations inevitably accumulate with age in the complete absence of carcinogens, and in the complete absence of inherited mutations.

That baseline rate of somatic mutation accumulation is of course accelerated by a host of environmental factors, including sun exposure, smoking, unhealthy eating habits, and exposure to any of a myriad of toxins that we inevitably experience in this highly industrialized world. To name just a few. Given a baseline rate of mutation accumulation and the acceleration by environmental carcinogens, even those of us with the healthiest lifestyles will have accumulated countless somatic mutations by the age of forty. Moreover, of those 30 trillion cells, if you were to pick one at random, odds are that it would exhibit one or more somatic mutations. Why do these cells so rarely go off the rails?

Not all mutations are created equal of course. Those that occur in certain housekeeping genes, called oncogenes, and others called tumor suppressor genes, are potentially more problematic. But even mutations of oncogenes that cause their upregulation, or tumor suppressor genes that cause their down regulation, are not sufficient causes of cancer, because the cells in which they occur are not independent actors, but rather, tightly constrained because of their integration with the other cells in the tissue in which they are embedded, and by cells in adjacent tissues. These tissue level constraints overwhelmingly influence what any particular cell can do, abnormally upregulated oncogenes or not. The qualities of the tissue environments determine the fate of cancerous cells and tumors (https://www.fredhutch.org/content/www/en/news/center-news/2022/08/how-cancer-does-not-happen.html).

BRCA

Let’s start with a notorious inherited mutation of a tumor suppressor gene, BRCA1. As has been widely publicized, some but certainly not all, mutations of this gene, greatly increase the risk of breast and ovarian--and prostate--cancers. But all the cells in our bodies have BRCA1 genes, so why don’t inherited mutations in these genes cause cancer more widely? For example, why don’t BRCA1 mutations cause skin cancers? It seems an obvious question to ask. But only quite recently have scientists begun to do so.

Here's a related consideration. When breast cancers metastasize, the unmoored cells are distributed throughout the body. Yet secondary breast cancer tumors only develop in a select few tissues and organs. The brain, unfortunately, is one. Lymphatic tissue is another. At this point I need to mention that cancer researchers have only relatively recently become aware that metastasis is common in even the earliest stages of tumor development (20501952). That is, tumor-derived cells can spread to other tissues long before late stage tumors develop. Most of those metastasized cells, though, don’t find purchase in suitable tissues; those that do usually become dormant in whichever tissue they find themselves, say the brain.

This dormancy is often described as a cancer cell’s way of outfoxing the new host cells. On this view, the metastasized cancer cell is lying low, seeking to avoid recognition, going incognito. A less anthropomorphic way to look at the matter is this: the metastatic cells are suppressed by other cells among which they now find themselves. This suppression can last decades, for the fortunate individual, a lifetime. In the brain, the suppression is accomplished by glial cells, called astrocytes. Far from “not recognizing” the invader, astrocytes actively keep it in check. Until they don’t, or rather, can’t. With age, the power of the astrocytes to keep a foreign cancer cell in check decays, just another symptom of age-related physiological decline.

Lymphatic tissue seems to provide conditions much more conducive for secondary tumors, breast cancers included, which is worth more investigation than it garners. I found it stunning to learn that some breast cancers are first detected in the lymph nodes, not the breast. In one study, in half of those cases, no tumor could be found in the breast, even after it was removed, and the tissue thoroughly examined at the cellular level(10.1002/1097-0142(19810615)47:12<2923::aid-cncr2820471231>3.0.co;2-n). Yet it had obviously sent out potential tumor cells body wide. Which brings us to occult tumors.

The Tumors Only Found After Death

In the opening, I posed the question “why aren’t cancers more common”?  In large part, the answer to that question is that the fate of cancer cells is largely determined by their tissue context as discussed above. But if, by “cancer”, we mean cancerous tumors, the answer is, well, the same. We are infested with many more tumors than are diagnosed. You and I may have small tumors somewhere in our bodies right now. But few will rise to the level of disease (or wound) status. Put another way, most cancers are wounds that heal. How? To answer that question, we need to take an even wider-angle view of cancer.

First, though, some facts unknown to most. From postmortem inspections of those who died of various causes unrelated to cancer, it was found that 34% of men in their forties have prostate carcinomas; 27% of men in their thirties; and 9% of men in their twenties (10.1016/s0022-5347(17)35487-3). The statistics are comparable for breast cancers in women (PMC2002422). Though prostate cancer is the leading form of cancer mortality in men, terminal forms of the disease are not remotely as common as these numbers would suggest. Something in prostate tissue is keeping them in check, for most of most men’s lives.

High occurrence rates of “occult” tumors have been found in other tissues, including the liver, pancreas, and lung. For thyroid glands, the incidence of occult tumors is so high that it is considered the norm (10.1002/1097-0142(19850801)56:3<531::aid-cncr2820560321>3.0.co;2-3. The skin of any adult is similarly rife with carcinomas that didn’t go anywhere. How is that? Context, context, and context. And by context, I mean tissue context.

Contextual tissue factors are especially evident in the skeletal muscle tissue. If cancer cells were agents, that is, goal oriented--which they emphatically aren’t--they would strenuously avoid skeletal muscles, the muscles that move your limbs, head and torso. Because skeletal muscle tissues are a hostile environment for cancer cells.

 As I alluded to in the previous post, skeletal muscles never develop secondary tumors. Or primary tumors, for that matter. Yet skeletal muscles would seem, on the surface at least, one of the more cancer friendly environments. Skeletal muscle cells are constantly regenerated from a pool of stem cells, called satellite cells, because of varied forms of tissue damage, even under normal usage. As in any wound, fibroblasts are activated, immune cells recruited, and blood vessels proliferate for the repair operations. Lactate, the stuff on which cancer cells feed, abounds in skeletal muscle tissue under standard operating conditions. Activated fibroblasts add additional lactate to the wound environment. You would think that these conditions would be encourage cancer invasion and growth. That skeletal muscle tissue is so cancer resistant is an indication that getting to the bottom of cancer is not synonymous with understanding oncogenes or tumor suppressor genes. We need to scale up, from genes to cells to tissues to organs to organisms. Signals arising at all these levels are integrated in the epigenetic landscapes of non-cancerous cells.