Evolutionary mechanism unifies the hallmarks of cancer

Abstract

The basis for the gene mutation theory of cancer that dominates current molecular cancer research consists of: the belief that gene‐level aberrations such as mutations are the main cause of cancers, the concept that stepwise gene mutation accumulation drives cancer progression, and the hallmarks of cancer. The research community swiftly embraced the hallmarks of cancer, as such synthesis has supported the notions that common cancer genes are responsible for the majority of cancers and the complexity of cancer can be dissected into simplified molecular principles. The gene/pathway classification based on individual hallmarks provides explanation for the large number of diverse gene mutations, which is in contrast to the original estimation that only a handful of gene mutations would be discovered. Further, these hallmarks have been highly influential as they also provide the rationale and research direction for continued gene‐based cancer research. While the molecular knowledge of these hallmarks is drastically increasing, the clinical implication remains limited, as cancer dynamics cannot be summarized by a few isolated/fixed molecular principles. Furthermore, the highly heterogeneous genetic signature of cancers, including massive stochastic genome alterations, challenges the utility of continuously studying each individual gene mutation under the framework of these hallmarks. It is therefore necessary to re‐evaluate the concept of cancer hallmarks through the lens of cancer evolution. In this analysis, the evolutionary basis for the hallmarks of cancer will be discussed and the evolutionary mechanism of cancer suggested by the genome theory will be employed to unify the diverse molecular mechanisms of cancer.

Heterogeneity‐mediated cellular adaptation and its trade‐off: searching for the general principles of diseases

“…This discovery thrusts the importance of genome stability into the spotlight, which also effectively unifies the diverse molecular mechanism to a more general evolutionary mechanism. More detailed discussion can be found in our cancer research literature . Cellular evolution is hard to predict (especially during a long process or when under high stress conditions that alters the genome) Neo Darwinian gradual evolution has dominated the field of cancer evolution for decades.…”

“…This discovery thrusts the importance of genome stability into the spotlight, which also effectively unifies the diverse molecular mechanism to a more general evolutionary mechanism. More detailed discussion can be found in our cancer research literature [9,16,[18][19][20][21]27,28].…”

“…Such increased heterogeneity will then feedback and alter all these cellular mechanisms in a stochastic fashion [1,8,15,37]. Recently, increased data have linked the elevated genome to many diseases and illness conditions, from cancer to Alzheimer's [9,[18][19][20][21][40][41][42][43][44]. We recently have also detected elevated non-clonal chromosome aberration (or NCCAs) in different illness conditions including Gulf War Illness and Chronic Fatigue Syndrome.…”

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

“…However, this list of common traits, each of which is a product of interactions of many molecular mechanisms, does not contribute much to the practical tasks of finding therapeutic approaches. Many of these mechanisms overlap, and are therefore unsuitable for the identification of proper therapeutic targets . The review by Fouad formulates yet another version of the hallmarks of cancer: “selective growth and proliferative advantage, altered stress response favoring overall survival, vascularization, invasion and metastasis, metabolic rewiring, an abetting microenvironment, and immune modulation” that support tumor progression…”

Elevatedde novofatty acid biosynthesis gene expression promotes melanoma cell survival and drug resistance

“…Elevated DNFA has been demonstrated in many tumor types 26 , including breast cancer 27 , prostate cancer 28 , and glioblastoma multiforme 29 . The prevailing thought is that hallmark traits, such as DNFA, arise chiefly as a consequence of pro-survival signaling pathways driven by genetic alterations of oncogenes and tumor suppressors [30][31][32][33] . Supposed dependence of tumor cells on a single oncogenic driver or pathway to sustain proliferation and/or survival has guided the development of targeted cancer therapies 34,35 .…”