We think of cancer as caused by mutations. Mutations are necessary, but not sufficient, to cause cancer. New research indicates that it’s the body’s response to mutant cells that determines whether cancer will develop. James S. Welsh, MD, a radiation oncologist and researcher, has written a book on the immunology of cancer, Sharks Get Cancer, Mole Rats Don’t: How Animals Could Hold the Key to Unlocking Cancer Immunity in Humans. In it, he pieces together clues from animals, pregnancy, Ebola virus, infections, organ transplantation, parasites, and human cancer patients, weaving a web of insights that point to a better understanding of cancer biology and treatment.
Sharks do get cancer
The first book claiming that sharks don’t get cancer came out in 1992. It persuaded so many people to take shark cartilage that the world market exceeded $30 million and shark populations decreased by as much as 80%. Sharks do get cancer, as you can see in this picture.
Ironically, sharks can even get cancer of the cartilage! And of course shark cartilage supplements don’t prevent cancer in humans. Welsh explains how that myth got started. It was magical thinking based on extrapolation from a legitimate scientific study on angiogenesis where tumor growth in lab animals was suppressed by placing rabbit cartilage next to the tumors.
Mole rats don’t
The naked mole rat (which is neither a mole nor a rat) may be the world’s ugliest animal. It has been compared to a miniature pink walrus, a saber-toothed sausage, and a bratwurst with teeth.
Naked mole rats have a number of unusual features: low oxygen consumption, an ability to slow their metabolism, a variable body temperature, and skin insensitivity to pain. And they are immune to cancer. If only we could understand how they accomplish that, we might be able to apply the knowledge to prevent cancers in humans. There are some clues. They have massive hyaluronan molecules that physically space their cells apart, they have a p16-mediated aversion to cellular crowding, and their biochemical protein synthesis mechanisms are unusually error-free. Their cells are also resistant to death by apoptosis and are more likely to undergo necrotic cell death.
The dreaded, ferocious, and cancer-free naked mole rat
Cancer immunity is also found in specially bred lab mice that overexpress a cancer-fighting gene called PAR4. Gene expression of PAR4 can be stimulated in other animals by a secretagogue. There is also a natural mutant “mighty-mouse” that passes on cancer resistance by autosomal dominant inheritance. These mice rarely get cancer, and if they do, it spontaneously regresses. And when white blood cells from mighty-mice were injected into mice with advanced cancers, it cured them! We can’t give mouse blood to humans, but understanding what is happening here could eventually lead to human treatments.
Abscopal effects
Welsh tells us about two of his own patients whose terminal cancer was treated with local radiation for palliative purposes only. He was amazed to see all evidence of cancer vanish from the entire body, a rare phenomenon known as the abscopal effect. Abscopal means “away from the target,” where local treatment causes a systemic response. Spontaneous remissions can occur even in the most advanced metastatic cancer. If only we could understand what is happening in those cases and harness it!
Cancer is not contagious
Scientists have always maintained that cancer is not contagious. You can’t catch it like you catch a cold. But it turns out you can catch it if you are a Tasmanian devil. The population of Tasmanian devils has been decimated by devil facial tumor disease (DFTD) a cancer that is passed from animal to animal through bites. The tumor is a bizarre new life form that has achieved immortality by passing itself on from individual to individual like some alien parasite. No other cancer is contagious in this sense; but as many as 15% of cancers are caused by viruses that are contagious, like HPV and hepatitis B.
Dogs get a contagious cancer called canine transmissible venereal tumor (CTCT). It is sexually transmitted and affects the penis. It accounts for up to 29% of all dog tumors in places like India where neutering is not common. Interestingly, it often undergoes spontaneous and permanent remission. In healthy adult dogs it typically progresses for 2-6 months, is stable for a while, and then regresses. In immunosuppressed dogs, it continues to grow and it metastasizes. It is exquisitely sensitive to radiation, and a radiation cure leaves the dog permanently immune to this type of cancer. It can pass to other species including coyotes, foxes, and jackals, which is really weird because of the barriers posed by the major histocompatibility (MHC) system. It has been suggested that the MHC system might have evolved to prevent tumors from being transplanted and that without it, contagious tumors might be more common.
Don’t blame cancer on modern lifestyle
Cancer is not a disease of civilization or of modern lifestyles. It’s a fact of nature. It’s been around at least since the Cretaceous: dinosaurs got it. It has been demonstrated in the remains of early humans. 50% of domestic dogs get cancer by the age of 10. Clams get cancer. Tapeworms get cancer (and that cancer has been known to spread throughout the body of their human host). Plants get cancer, although their rigid cell walls prevent metastasis.
Lessons from parasites
Cancer can be thought of as a sort of unsuccessful parasite that dies when it kills its host. The cancer in Tasmanian devils has found a way out. Perhaps we can find clues in the behavior of other parasites. The Ebola virus escaped from a natural reservoir to infect human hosts, where it is very successful at propagating itself. It first silences the immune cells intended to detect and destroy it. It lulls them into inaction until it is too late; then when they finally wise up, they overreact with a cytokine storm that does more harm than good. Those in the 15-45 age group, the group with the strongest immune systems, are the most likely to die.
Clues from organ transplants
Sometimes cancers are inadvertently transplanted along with organs. If the immunosuppressive treatment is stopped, the cancer ought to be rejected along with the transplanted organ. But it isn’t. It seems to have developed a cloak of invisibility. In one case, a man died of ovarian cancer after a transplant from a woman.
In another case, a kidney donor had been treated for melanoma 32 years earlier and was considered cured, but melanoma was transplanted along with the kidney; apparently he had been sheltering a few malignant cells in his kidneys all those years.
There is an increased risk of cancer with transplantation and lifelong immunosuppression. Squamous cell skin cancers in transplant patients behave differently: they metastasize and are very aggressive.
These are tantalizing clues to something, but what?
Coley’s toxins: sometimes they worked!
After severe infections, tumors sometimes regress. In the 1890s, William Coley experimented with injecting streptococcal organisms into patients with advanced cancers. His patients usually developed a severe infection with high fevers, and many of them died; but a few survived and became cancer-free. “Coley’s toxins” were discredited and abandoned, but the possible mechanisms for his inconsistent successes are being looked at again.
Is cancer a disease of aging?
It’s logical that the older you get, the more likely you are to develop cancer, because you have had more time to develop mutations; but what if the association of cancer with aging is due to a waning of immunity with age? What if we are constantly developing cancer cells that are being suppressed by our immune systems? Perhaps some are being eliminated and some are merely being kept under control so we can live with them without harm.
Are we asking the wrong questions? Instead of asking why smokers are more likely to develop lung cancer, maybe we should ask why most smokers don’t get it, and why Uncle Joe remained in good health to the age of 102 despite smoking, drinking, eating junk food, and being exposed to toxins. Why are some people resistant to cancer? There is an autosomal-recessive hereditary condition called Laron dwarfism where the affected people never get cancer. What’s more, they don’t develop diabetes despite being obese.
Pregnancy
In pregnancy, a fetus must escape immune surveillance and not be recognized as “foreign.” The mechanism is not well understood, but it seems that the placenta acts as an immune regulatory organ to protect the embryo. There is a rare condition called a hydatidiform mole where an “empty” ovum is fertilized by sperm. 15-20% of these become malignant. But they have no maternal DNA; they are entirely foreign male tissue. Why are they not rejected by the immune system? Molecules are being discovered that are common to both fetal protection and cancer protection. In the microenvironment of the cancer, the immune system acts to protect the cancer just as the placenta protects the fetus.
Conclusion: A great book about a terrible scourge
This is an outstanding book. It combines a fun trip to the zoo with an introductory course in cancer immunology. It’s full of weird facts that you can repeat as trivia to impress your friends. I could only sample its riches here. There is much more in the book, with details and copious references. The subject is endlessly fascinating, and the writing style is clear, appealing, and accessible, broken into 36 short, easily-digested chapters. This is cutting edge hypothesis-generating science pointing to exciting discoveries sure to come in the near future.
As Dr. Welsh concludes:
Years of skepticism about cancer immunotherapy are finally fading… The revolution is on!
This article was originally published in the Science-Based Medicine Blog.
