by Marcia Stone
Editor’s Note: This is the second in what is expected to be an ongoing series about cells that might not come immediately to mind when you think “microbe.” The first is linked here Oddly Microbial: Ribocytes. Comments and suggestions are encouraged.
“Cancer cells are ancient alternative organisms, living protozoan-like fossils, foreign to their hosts because of deep origins elsewhere,” says oncologist Mark D. Vincent from the University of Western Ontario in Canada. They are, he asserts “In the body but no longer of the body,” and therefore deserve a radically different taxonomy. This isn’t a new idea but one taking on increasing relevance with the dismal failures of one onco-therapy after the other.
Cancer is not simply a “disease,” Vincent argues, “It’s a competitive struggle between a battle-scarred ‘protozoan’ from the Pre-Cambrian era and its ‘normal’ metazoan phenotype.” The cancer cell resembles a type of opisthokont, our uniciliated eukaryotic ancestors which are closely related to choanozoa and fungi. Moreover, despite the need for cancer cells to inhabit metazoa, malignancy isn’t integral to multicellularity. Indeed, for cancer cells to succeed they have to forsake membership in their host. This entails the usual microbial tactics of immune evasion, nutrient competition, autophagy enslavement, and, ultimately, tissue invasion. “Paradoxically, the more resilient the cancer, the more likely it is to self-destruct by killing its host,” says Vincent.
However, carcinogenesis can promote long-term survival if vast numbers of cancer cells escape the dying metazoan into a moist environment and either achieve a free-living future or parasitize another host, Vincent explains. The best known examples of the latter are infectious malignancies such as canine transmissible venereal tumor (CTVT) and the deadly facial cancer that afflicts the Tasmanian Devil. “These cancers are able to evade the mortality of both their original and their new temporary hosts in exactly the same manner as an extrinsic infectious microorganism,” he adds but emphasizes that interpersonal transmission of cancer cells is rare and the evolutionary “deep origin” theory involves “a much more sinister concept of encrypted cancer cells in modern genomes.”
That cancer cells can survive as free-living cells is speculative, but Vincent notes that they grow extremely well in fluid-filled body cavities (ascites, pleural effusions, cerebrospinal fluid and the like). Thus, carcinogenesis could represent a vestigial aquatic behavior that is still successful for unicellular eukaryotes and simple metazoa.
“If an enterprising early cell ‘judged’ its metazoan was doing poorly, oncogenic reversion and host sacrifice could provide an escape from imminent death,” according to Vincent. This strategy is not unknown in nature; for example, even little bits of genes called superantigen pathogenicity islands, or SaPIs, routinely escape their doomed phage-infected bacterial hosts in search of cells with brighter futures.
Successful life forms—everything still around today—had to have an evolutionary “Plan B” and Vincent considers cancer cells Plan B: proto-organisms encrypted in every eukaryotic cell in every multicellular animal retained to deal with periods of extreme challenge. The sole purpose of this latent life form, according to Vincent, was “to invent its way to the future” during early Earth’s episodes of pre-ozone, extraterrestrial irradiation; food chain collapse and nutrient deprivation; inter-species chemical competition; a deluge of reactive oxygen species (ROS) and unpredictable climate extremes. Thus, “The universal traits exhibited by cancer cells represent the re-emergence of an ancient survival program,” he says. These traits include immortality, genomic instability, unicellularity, asexuality, maturation blockage, and fermentation.
However, the resilience necessary to sustain life on early Earth has a “dark side” for modern-day metazoans, Vincent says, pointing to “the survivability of the cancer lineage and its profound defense capabilities against a range of extreme therapeutic toxins and radiation. “Moreover, the environments within which cancer cells flourish, those with intolerably low oxygen and pH, resemble the Pre-Cambrian dooming to failure therapies that closely resemble the same challenges cancer cells evolved to defeat, i.e. radiation, antimetabolites, and anti-tumor antibiotics.
Recognizing cancer as a species separate from the metazoan host rather than just a series of random cellular mistakes is cause for optimism because it guarantees distinct molecular targets for rational drug design. Like other microbes, for example, cancer cells grow in colonies; cooperation and competition require communication. Thus, targeted quorum-sensing antagonists might be designed and deployed to break up tumors, which are akin to biofilms. It’s also possible that the strategies developed to defeat cancer-cell proliferation could be extended to other yet unconquered protozoan parasites as, for example, Plasmodium falciparum, the deadliest cause of malaria.
Perhaps there is even a cancer “off switch,” Vincent says and suggests that we devote more resources to looking for it.
“Vincent’s thesis that cancer is our evolutionary heritage is a fascinating complement to the distillations of Douglas Hanahan and Robert A. Weinberg, which imply that cancer is driven into a state of unrestrained growth by forward evolution,” comments Garry P. Nolan at Stanford University. “At the core of every cell’s regulatory apparatus is the ‘will to live,’ a restrained program waiting to be let loose once the social contract with the metazoan is broken—a primordial program waiting to be unleashed. Not only do mutations drive cancer forward, they simultaneously set free an embedded survival program,” says Nolan. “This idea has an engaging symmetry and although difficult to prove from an evolutionary perspective, prototypical examples might be found in more primitive metazoans,” he adds.
Marcia Stone is a science writer based in New York City and a frequent contributor to ASM’s Microbe magazine.