New cancer diagnostics and therapeutics from a ninth ‘hallmark of cancer’: symmetric self-renewal by mutated distributed stem cells

Abstract

A total of eight cellular alterations associated with human carcinogenesis have been framed as the ‘hallmarks of cancer’. This representation overlooks a ninth hallmark of cancer: the requirement for tumor-originating distributed stem cells to shift sufficiently from asymmetric to symmetric self-renewal kinetics for attainment of the high cell production rate necessary to form clinically significant tumors within a human lifespan. Overlooking this ninth hallmark costs opportunities for discovery of more selective molecular targets for development of improved cancer therapeutics and missing cancer stem cell biomarkers of greater specificity. Here, the biological basis for the ninth hallmark of cancer is considered toward highlighting its importance in human carcinogenesis and, as such, its potential for revealing unique molecules for targeting cancer diagnostics and therapeutics.

Keywords::

• asymmetric self-renewal
• distributed stem cells
• immortal DNA strands
• non-random segregation
• p53 mutation
• symmetric self-renewal
• tissue cell turnover

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • As an obligatory factor in the development of many human tumors, the conversion of DSCs from tissue cell homeostatic asymmetric self-renewal kinetics to exponential symmetric self-renewal kinetics is presented as a ninth hallmark of cancer.

• • The ninth hallmark of cancer, symmetric self-renewal by mutated DSCs, is a rate-limiting factor for the tumorigenic effects of the previously described eight hallmarks of cancer.

• • Increased adoption of ideas and concepts from the ninth hallmark is predicted to accelerate progress in cancer research and provide new opportunities for advances in cancer biomedicine, including prevention, diagnostics and therapeutics.

• • Many tissues are organized as arrayed replicate units with a hierarchal cell kinetics structure that, throughout the lifespan of multi-cellular organisms, produces short-lived, non-dividing, differentiated cells along a physical vector initiated by actively asymmetrically self-renewing DSCs.

• • Whether DSCs in different tissues accomplish asymmetric self-renewal by either stochastic or deterministic cell kinetics programs continues to be a highly challenging unresolved question in vertebrate stem cell biology.

• • Non-random sister chromatid segregation is a DSC-specific form of mitotic chromosome segregation that occurs primarily during asymmetric self-renewal and is proposed to reduce DSC mutation rate. Therefore, the ninth hallmark, a shift from asymmetric self-renewal to symmetric self-renewal, also causes DSCs to shift from non-random segregation to random segregation, which is predicted to cause the loss of an important defense mechanism against the accumulation of carcinogenic mutations.

• • The evolution of non-random sister chromatid segregation by DSC favors the operation of deterministic asymmetric self-renewal programs by DSC, because the proposed evolutionary advantage of reduced gene mutation rate provided by non-random segregation cannot be realized with stochastic asymmetric self-renewal programs.

• • DSCs are the likely most frequent cell of origin for human cancers, and, as such, in many cases they may also be the ancestors of CSCs. The cancer therapeutic implications of this possible genealogical relationship are an example of how future emphasis on ideas derived from the ninth hallmark concept could beneficially impact cancer biomedicine.

• • Though an evident essential factor in carcinogenesis, realizing the full potential of the ninth hallmark of cancer concept will require a significant mobilization of resources to address challenging questions and problems in human DSC and CSC biology.

Notes