The role of host environment in cancer evolution

Abstract

Somatic mutations in oncogene and tumor suppressor genes accumulate in healthy tissues throughout life and delineate clones with limited expansion. Lifestyle‐related toxic insults increase the size and number of these clones that participate to tissue aging. Their identification has blurred the boundaries between clonal expansion and malignant tumor and has drawn more attention to the role of the host environment in tumor emergence and progression. Local tissue factors such as disrupted cell interactions and stromal cell senescence combine with systemic and distant alterations to initiate the reiterative process of clonal expansion, multilayer intrinsic diversification and clonal selection that eventually characterize overt tumor evolution. In turn, tumors remodel their close and distant environments, establishing positive feedback loops that contribute to disease progression. Strategies emerge to preserve the tumor suppressive properties of healthy tissue landscapes and delay age‐induced changes that eventually lead to cancer.

Multiple Myeloma as a Bone Disease? The Tissue Disruption-Induced Cell Stochasticity (TiDiS) Theory

“…The TiDiS theory can be viewed as an alternative explanation to the overly autonomous "chromosome-centric" standard model. This causal concept strongly supports MM (in particular, but cancer in general) not only as an evolutionary multistep process but also as an ecological (environmental tissue dependent) process in which a critical initiating/promoting role is devoted to an environmental niche of significance and its disruption [19][20][21].…”

“…We would like to go further by providing a theory giving bone/BME a potential role in the initiation of MM, which may ultimately lead to therapeutic perspectives. Several arguments can now be formulated against a unique initiating role of genetic alterations because alterations of the host environment could also contribute to the emergence of tumors [21]. For instance, oncogenic mutations are not sufficient to start transformation; oncogenesis can initiate from disruption of the BME, and cancer cells harboring multiple genetic alterations can be controlled and reverted by a healthy tissue environment [21,[63][64][65].…”

“…More precisely, according to the TiDiS concept, a goal of the treatment will be to act on the BME to "re-educate" it, in order to restore the cellular interactions present in the initial tissue, so as to control cells by restabilizing their phenotypes. Much experimental evidence indicates that the normal microenvironment is able to control genetically altered cells and reduce phenotypic plasticity [21,[63][64][65]71]. Thus, mimicking this normal micro-environment with molecules that would mimic healthy cellular interactions, together with molecules stimulating the re-expression of the proteins necessary to interact with these partners, would be efficient in stopping cell proliferation and cancer evolution [60,74].…”

A Similar Speciation Process Relying on Cellular Stochasticity in Microbial and Cancer Cell Populations

“…If genetic alterations are already present, they would accelerate the process, but it can be considered that the process can start without driver mutations. Multiple examples showed that oncogenic mutations are not sufficient to start transformation ( Martincorena et al., 2015 ; Yizhak et al., 2019 ; Yokoyama et al., 2019 ), that oncogenesis can initiate from disruption of the micro-environment ( Kode et al., 2014 ; Maffini et al., 2004 ; Raaijmakers et al., 2010 ; Walkley et al., 2007 ), and that cancer cells harboring multiple mutations can be controlled and reverted by a healthy tissue environment ( Booth et al., 2011 ; Bussard et al., 2010 ; Hochedlinger et al., 2004 ; Rubin, 2006 ; for review, see Solary and Lapane, 2020 ).…”

The Erlang distribution approximates the age distribution of incidence of childhood and young adulthood cancers

“…We define driver events as discrete molecular alterations that provide the cancer cell of origin and the resulting clone the necessary means to overcome both the intracellular and extracellular tumor suppressor mechanisms, such as cell cycle checkpoints, contact inhibition, immune surveillance, and promote growth in the absence of growth factors. Thus, our concept of a driver event integrates mutational, microenvironmental, immune and evolutionary perspectives ( Rozhok & De Gregori, 2015 ; Solary & Lapane, 2020 ). It is also important to note that only the winner clone’s evolutionary history determines the time of tumour appearance and thus the kinetics of cancer incidence; therefore, any mention of driver events in this article would always refer to driver events in the winner clone.…”