Cancerul, o problemă nerezolvată

With its March 28, 2014 title cover: “Solving Cancer/You Can’t Cure What You Don’t Understand”, “Newskeek” magazine posited the idea that our failure to cure cancer comes from our lack of grasping its full complexity. In an attempt to find the ever elusive panacea for cancer, contemporary science has put forth three main paradigms that I will describe briefly.

1. The xenobiont. “Cancer is an alien”. Over the last four decades, cancer has been considered principally a genetic disease and the research focus has been to characterize the nature and number of genes associated with oncogenesis. Today, it is clear that at the genetic level, each individual cancer has a unique make-up harboring idiosyncratic genetic alterations⁽¹⁾. Some of these genetic alterations are called “drivers” because they “drive” the oncogenic process and the cancer cells become “addicted” to them. Since Paget’s “magic bullet“ concept, the main strategy in research has been the Nixonian “war on cancer”, which strove to define and target the idiosyncratic features of “the enemy.” . One of the most cited article was published in 2000 in “Cell”⁽²⁾ by Hanahan and Weinberg. The authors see cancer as comprised of cells with “defects in regulatory circuits that govern normal cell proliferation and homeostasis” and as having six characteristic traits that develop progressively during the course of cancer progression. “We suggest that the vast catalog of cancer cell genotypes is a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth: self-sufficiency in growth signals, insensitivity to growth-inhibitory (antigrowth) signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion”. In a subsequent article published in 2011⁽³⁾, the two authors expanded the number of cancer specific characteristics to ten, adding to the list four other hallmarks: genetic instability and mutation, tumor promoting inflammation, avoiding immune destruction and deregulated cellular energetic. Because of the authoritative impact of this paper, these hallmarks are usually quoted as the starting ground for new anticancer strategies. The initial list of hallmarks has been criticized and justly so, as five of them (self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis) are shared with benign tumors⁽⁴⁾. On the other hand, the cancer hallmarks, even if partially shared by benign tumors, can be seen as what makes cancer cells stand out from the normal cells. The idea of cancer as being radically different has been recently pushed to extreme by Mark Vincent from the University of Western Ontario, who describes cancer a “protozoan-like organism”, “foreign to its host”, growing inside the human body^(5,6,7). Like an alien unicellular life form, a xenobiont arises out of the reactivation in the genome of an “ancient de-repressed survival program”. According to him, cancer represents the return to a unicellular life form, a sort of regression to an “ancient and alternative organism, a living fossil, foreign to its host”. The core component of this “re-primitivization” process in which the cells return to an “ancient, de-repressed survival program” is in Mark Vincent`s view the metabolic switch to aerobic glycolysis (the Warburg phenomenon).

There is a logical connnection between the model of cancer as a xenobiont and the idea of the “magic bullet”; if cancer would be completely different from the normal organism, the idea of destroying cancer with surgical precision without affecting the normal organism seems reasonable. The success and pitfalls of targeted biological agents developed over the last two decades are a direct proof of the clinical value of this paradigm. Cancer cells may indeed be different from the normal cells but it turns out that there is a large heterogeneity present also among the cancer cells themselves. In a recent article in „Nature”⁽⁸⁾, Wang et al. sequenced the genomes of individual cells from two types of cancer and did not find any two individual cells that were genetically identical. In real life, the analogy of the xenobiont may be misleading because in many cases cancer contains multiple clones that may be different from each other; a variety of different xenobionts is involved in the cancer process and these xenobionts evolve continuously and interact with each other. So the xenobiont paradigm may be true but, ultimately, useless in most cases; cancer cells may contain different features from the normal cells but these features are not universally shared between the cancer cells themselves. Targeting a non-universal cancer feature may lead in the long run to resistance due to the proliferation of cancer clones that do not contain the targetable feature. For example, targeting the Warburg phenomenon, as suggested by Mark Vincent`s model, may lead indeed to the destruction of the cancer cells clones using aerobic glycolysis but may not affect the cancer cells that use oxidative phosphorylation or  other types of metabolic substrates for their survival (for example, cancer cells thriving on glutamine). Finally, the xenobiont paradigm should not make us forget that cancer cells derive from normal cells and they are, as Harold Varmus said “a distorted version of our normal selves”.

In 2015 it is time to rethink the xenobiont paradigm and use it in novel ways. For example, recently, a group of researchers from UK suggested that cancer should be treated as an infectious disease and destroy selectively the cancer stem cells using antibiotics⁽⁹⁾.

2. The symbiont. “Cancer is a parasite”. Robert Gatenby, at the Moffitt Cancer Center, proposed to “make peace” on cancer, and invented a novel anti-cancer approach called “adaptive therapy”⁽¹⁰⁾. This anti-Nixonian strategy consists in the continuous administration of smaller than usual chemotherapy doses, in metronomic-like fashion, that would not completely eradicate the cancer cells, but it would prevent resistant clones from developing; thus, creating a parasite-host symbiotic state between the cancer cells and the normal organism. An example of the symbiotic approach is the use of maintenance treatment after achieving stable disease.

3. The oncobiont. “Cancer is an altered cellular program”. The current paradigm sees cancer as a chaotic disorganization of the cellular functions caused by random genetic mutations subjected to Darwinian selection. The oncobiont paradigm considers the changes that occur inside the cancer cell as non-random transformations due to the switch to a modified cellular program that can be re-written or re-run differently, leading to a non-neoplastic state. Such “reprogramming” could bypass the genetic abnormalities present in cancer through rerouting the cancer cell phenotype to a benign phenotype⁽¹¹⁾. In 1959, in a series of experiments, Pierce and collaborators transplanted teratocarcinoma cells into mice and noticed that the tumor cells can differentiate into benign tissue^(12,13). Subsequently, it has been shown in several nuclear transfer experiments that it is possible to revert the malignant phenotype of a cell to a non-malignant phenotype. Nuclei from malignant cells are reprogrammable if placed in a different environment. This finding supports the idea that epigenetic conformation of a tumor cell may determine whether a cell manifests a malignant phenotype or not⁽¹⁴⁾.

Despite the fact that these experiments took place more than half a century ago and they have been replicated in dif­ferent cancer cell models many times⁽¹⁵⁾, the field  of genetic reprogramming is still in its infancy and the mechanisms by which cells in a multicellular organism are constrained to adopt a certain state are still not well understood. 

If cancer cells can be reprogrammed, such reprogramming could bypass the genetic abnormalities present in cancer through rerouting the cancer cell phenotype to a benign phenotype.

In an article published in „Nature Reviews of Cancer” in March 2009, Adam Telerman and Robert Amson, two researchers from École Normale Supérieure in Paris, France, that have been modeling tumor reversion for more than 20 years, stated that the “reversion process involves a reprogramming mechanism using genetic and probably epigenetic tools that will supersede the changes in cancer by assembling and triggering alternative ways leading to the suppression of tumorigenicity”⁽¹⁵⁾.

A succesful oncobiontic intervention is the use of all-trans retinoic acid (ATRA) in acute pro-myelocytic leukemia (APL).

The above three paradigms are informative and should be integrated in carefully orchestrated interventions, such as: a) targeting the idiosyncrasies of cancer, b) inducing a symbiosis between cancer and the normal organism, and c) designing signals able to “modify” the cancer program.  Applying these approaches in the appropriate clinical setting, hopefully, will improve the prognostic of cancer patients.