Toward a general evolutionary theory of oncogenesis

Abstract

We propose an evolutionary framework, the barrier theory of cancer, which is based on the distinction between barriers to oncogenesis and restraints. Barriers are defined as mechanisms that prevent oncogenesis. Restraints, which are more numerous, inhibit but do not prevent oncogenesis. Processes that compromise barriers are essential causes of cancer; those that interfere with restraints are exacerbating causes. The barrier theory is built upon the three evolutionary processes involved in oncogenesis: natural selection acting on multicellular organisms to mold barriers and restraints, natural selection acting on infectious organisms to abrogate these protective mechanisms, and oncogenic selection which is responsible for the evolution of normal cells into cancerous cells. The barrier theory is presented as a first step toward the development of a general evolutionary theory of cancer. Its attributes and implications for intervention are compared with those of other major conceptual frameworks for understanding cancer: the clonal diversification model, the stem cell theory and the hallmarks of cancer. The barrier theory emphasizes the practical value of distinguishing between essential and exacerbating causes. It also stresses the importance of determining the scope of infectious causation of cancer, because individual pathogens can be responsible for multiple essential causes in infected cells.

Infection and cancer in multicellular organisms

“…From an evolutionary perspective, most cells within a body are moulded by natural selection to inhibit these processes and thereby enhance the fitness of the organism to which they belong. In this context, oncogenesis is largely the breaking of this regulation so that individual cells can replicate themselves and spread, increasing their numbers at the expense of the fitness of the organism [16]. If the genetic instructions for mobility, spread and invasion are not already present in plant genomes (because plants do not have mobile, invasive cells as components of their defences and development), then agents of cancer (whether infectious or non-living) cannot unmask these instructions.…”

“…Infection may contribute to cancer indirectly, for example, when inflammatory responses increase mutations or proliferative signals [12][13][14][15]. Alternatively, infectious agents may contribute to cancer directly by encoding proteins that compromise cellular barriers to oncogenesis, such as cellular regulation of telomerase, apoptosis, cellular adhesion or cell-cycle arrest; or cellular restraints on oncogenesis, such as control of proliferation rate [16]. These characteristics evolve particularly in intracellular pathogens not because cancer is beneficial to infectious agents but apparently because these attributes increase the ability of these pathogens to reproduce within hosts with reduced exposure to immunological destruction [17].…”

“…Oncogenicity has arisen independently in different viruses, which invoke different molecular mechanisms to abrogate the same cellular barriers to oncogenesis; these mechanisms and their effects of cellular proliferation and immortalization are understood in great detail (reviewed by Ewald & Swain Ewald [17]). The oncogenicity of these viruses therefore appears to result from natural selection acting on the viruses to force host cell replication, thereby enhancing the propagation of the viral genomes under the constraint of immune surveillance [16].…”

Evolution Theory: Its Practical Relevance for Understanding Tumor Development and Specifying Tumor Therapy

“…A currently published 'evolution theory' proposes as evolutionary benchmarks some deeply grounded biological perspectives, i.e., 'natural selection acting on multicellular organisms to mold barriers and restraints, natural selection acting on infectious organisms to abrogate these protective mechanisms, and oncogenic selection which is responsible for the evolution of normal cells into cancerous cells' [98]: This way, biological systems disintegrate in the particularism of suggested relevant cuttings of the 'living world' in the sense of a neopragmatism. An evolution theory allows a possible virtualization of the engagement to get (therapeutic) decisions via implementation of non-normative boundary conditions…”

Expression of CD133 in various premalignant and proliferative lesions

“…The types of CCSC are CD133, CD24, CD44, CD26, ALDH, and others. 8,9 CD133 is a hematopoietic stem cell that is cholesterol interacting penta-span transmembrane glycoprotein (120kd), play a role in tissue regeneration, inflammation and tumors. 10,11 The function of CD133 is unknown, but is expressed in biological stress.…”