Some people worry about getting cancer continuously. Their fear of cancer rises to the level of an overt phobia known as cancerophobia. It is an active behavior related to the dread of cancer that may lead to repeated medical examinations that fail to reveal a malignancy. Despite this, people with this condition are unable to be reassured about their clean bill of health for any length of time.
Luckily, most of us are not overtly phobic about cancer even though it may be lurking deep in our subconscious. Why is it not an active fear for the bulk of the population? It is likely because in people without any signs of cancer, it is not perceived as an imminent threat.
We are hard-wired to fear clear and present dangers. Risks and threats far into the future don’t get as much priority in our constellation of daily fears.
Examples of this from our daily life abound. For example, one study found that most people are not willing to take urgent action on climate change if it is presented as a distant threat. But if portrayed as proximal in time and place, more people are willing to act with urgency.
This may seem unrelated to worrying about cancer but the underlying neurobiological mechanism is the same.
So, should we worry more about getting cancer?
George Klein, Professor Emeritus at the Microbiology and Tumor Biology Center at the Karolinska Institute in Stockholm, Sweden, has been a teacher and a researcher since the mid-1940s. He published a fascinating article in The Scientist that makes the point that approximately 1 in 3 people will be struck by neoplastic disease in his or her lifetime. But, the other side of that coin is that two out of three people remain unaffected. Even the majority of heavy smokers who bombard their lungs with carcinogens and tumor promoters over many years remain cancer-free.
Pathologists have shown that virtually all men aged 60 or older have microscopic prostate cancer when examined at autopsy. However, most of these micro-tumors never develop into overt cancer.
It is also known that circulating tumor cells (CTCs) are present in many cancer patients. However, only a portion of these cells will enter and persist in distant parts of the body. These are known as disseminated tumor cells or DTCs. An only a fraction of them develop into secondary tumors (metastases).
They are kept in check by a mix of the following elements:
- The immune system
- Factors related to the tissues of the body (“hostile microenvironments”)
- Factors related to the needs of the cancer cells themselves (epithelial cells need a basement membrane in order to grow).
In other words, when it comes to getting or not getting cancer, the glass is more than half-full. So, should we just relax and not worry?
That’s not a productive question to ask. A more interesting one, that may actually produce interesting answers is: What makes most people resistant to cancer?
What causes cancer?
Cancer is caused by damage to genes that accumulate over time. There are a number of ways this damage can occur including, but not limited to this list:
- Exposure to carcinogens, including those in tobacco smoke or in the environment (asbestos)
- Infections with certain viruses or bacteria (hepatitis B or Epstein-Barr)
- Radiation exposure
- Some drugs, such as medications that weaken the immune system
- Genetic predisposition (for example Lynch Syndrome)
- Factors not yet identified
We know that colon cancer, breast cancer, and prostate cancer, develop through progressive stages of mutations that ultimately cause cell division to spin out of control and proliferate wildly.
So is cancer resistance simply the other side of the coin, namely the lack of harmful mutations? Put in those terms, is not getting cancer simply a matter of luck? But to paraphrase Albert Einstein’s quip about quantum mechanics, evolution doesn’t play dice; it increases its odds with natural selection.
It turns out that mutations, harmful or otherwise, occur all the time in all of us. But, we all (with few exceptions of genetic or pathological conditions) possess several well-known mechanisms for active resistance to cancer.
The body’s anti-cancer mechanisms
In an important paper published in PNAS, George Klein identified five kinds of anti-cancer mechanisms:
The first type is immunological. For example, researchers have compared the antibody responses of the squirrel monkey and the marmoset when infected with Herpesvirus saimiri. Marmosets, but not the squirrel monkeys, develop rapidly growing lymphomas after exposure to the virus. Of note, the virus is endogenous to squirrel monkeys, but marmosets never encounter it.
The researchers found a striking difference in the timing of each animal’s antibody response. In the tumor-resistant squirrel monkeys, the antibodies rose to a high level just three days after the infection. In the marmosets, however, the response took three weeks, too late to stop the virus-driven lymphoma.
The dynamics of the antibody response suggest that squirrel monkeys had pre-existing memory T cells against the virus. Whereas the marmosets had to develop them first before a full-blown antibody response could be mounted, a process that takes about three weeks.
The second mechanism Klein describes is genetic. Our cells are constantly subjected to DNA damage. And, there are individual variations in the efficiency of the repair mechanisms.
Although, in the vast majority, these mechanisms are capable of repairing the damage quickly, some are not. An example is a DNA repair deficiency disorder called xeroderma pigmentosum. Individuals with this deficiency are highly sensitive to ultraviolet light. Even with careful protection, they develop multiple skin cancers due to their genetic deficiency.
The third mechanism is epigenetic. This involves changes in gene expression, rather than changes in the DNA itself.
DNA methylation is one of the key epigenetic factors involved in regulation of gene expression and genomic stability. It is biologically necessary for the maintenance of many cellular functions.
Genomic hypomethylation is common in both solid tumors such as prostate cancer, hepatocellular cancer, cervical cancer, as well as in hematologic cancers such as B-cell chronic lymphocytic leukemia.
The next two mechanisms are, for some reason, my favorites.
4. Apoptosis or cell death
As part of an intracellular defense, a cell can trigger apoptosis, or cell death, if it detects extensive DNA damage. This prevents the cell from reproducing and spreading the damage. It is the ultimate altruism on the cellular level.
In some individuals, this mechanism fails. The cellular protein P53 is a tumor suppressor. When it is mutated, it increases the risk of inheriting Li-Fraumeni syndrome, a rare disease in which patients develop multiple tumors.
5. Factors in the tissue’s microenvironment
The last mechanism of defense against tumors resides in the microenvironment in which tissues are embedded. Here is a striking example. The naked mole-rat (NMR) and the blind mole rat (BMR), live up to 20 and 30 years, respectively, and never develop cancer. How do they pull off this trick?
The naked mole-rat (NMR) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a rodent species. It is especially striking considering its small body mass. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years. In addition to their longevity, naked mole-rats show an unusual resistance to cancer.
The NMR is a social species that lives in highly organized matriarchal societies. It has to force its way through narrow and often sinuous underground tunnels. The connective tissue in its skin contains a high-molecular-weight form of hyaluronic acid (HA) that makes the animal’s skin malleable. The corresponding HA in mice and humans has less than one-fifth of the molecular weight.
The heavy form of HA that occurs in the NMR is not only beneficial for the animal’s locomotion. It also prevents the transformation of normal cells in cell culture into cancer cells. Only after it has been removed can the NMR’s cells be transformed into cancer cells. The NMR cells also display an extreme sensitivity to contact inhibition: The cells stopped dividing when barely touching each other.
Several species of the blind mole rats (Spalax judaei and Spalax golani) are common in Israel and surrounding countries. BMRs are small subterranean rodents. They are distinguished by their adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 years), and resistance to cancer.
In tissue culture, when overproliferation started taking place after several cell divisions, BMR cells began secreting interferon ß which triggered a massive cell suicide response (a.k.a. apoptosis). The Masada phenomenon is apparently alive and well in this Middle Eastern species.
In case you conclude that it is subterranean living or the small size that protects these animals from getting cancer, think again—the blue whale is cancer-free as well. So, we don’t have to live underground or go back to the ocean, where our very distant ancestors came from.
The bottom line is that most of us don’t need to worry about getting cancer
Rather, we can take a deep breath and relax because two-thirds of us will never develop cancer. As for the other third, don’t despair. Diagnostics and therapeutics for cancer are propagating at a rapid rate. That doesn’t mean all cancers are preventable or curable yet. But I, for one, am putting my faith in human ingenuity to one day make cancer less feared than it is today.
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Originally published 5/3/15, it was updated on 3/25/18. It was republished after a major revision on 11/9/19.