Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

Abstract

Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here we review data and technologies that have revealed intra-tumor heterogeneity across cancer types, and the dynamics, constraints and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis, and consider the role of the tumor microenvironment in engendering heterogeneity and drug-resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immunemicroenvironment whilst limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome.

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Indeed, based on the "seed and soil' theory of Paget, it is now well recognized that osteosarcoma, like other cancers, requires an adequate local microenvironment for its development [11,12]. This microenvironment can provide all metabolites and factors for the control of proliferation, drug resistance, dissemination or/and dormancy of osteosarcoma cells [5,[13][14][15]. Then, the pressure exerted by microenvironment may be responsible for a specific selection of osteosarcoma cells with predominant specificities such as a high quiescent or a proliferative profile.…”

Meiosis-like Functions in Oncogenesis: A New View of Cancer

“…The ALT pathway operates via a recombination-mediated mechanism in which, in the absence of normal telomerase-mediated elongation, telomeres behave like a broken chromosome end, serving to stimulate RAD51 recombinasemediated strand invasion of an uncapped telomere into a nonsister telomere to enable the invading end to serve as a substrate for DNA replication-dependent de novo telomere elongation (35). This phenomenon can not only help drive tumor formation but also enables tumor cell proliferative activity and is likely to contribute to tumor cell evolutionary potential (36,37), although this latter point requires experimental exploration.…”

“…For example, gene expression regulation does change, but it is not done in a programmed and preordained temporal fashion, as would be the case during embryogenesis. Rather, tumor cells have the capacity to undergo a relatively rapid genomic and epigenetic evolution over time in response to the immediate requirements and pressures of the tumor/tumor cells (36,37,70). Indeed, tumor cells deviate considerably from the normal cellular constraints that control embryogenesis, such as apoptosis and telomeric regulation.…”

Challenges and unanswered questions for the next decade of circulating tumour cell research in lung cancer

“…More recently, NGS technologies have been used to understand the breadth and depth of this overwhelming genetic diversity in primary and the metastatic tumours (74)(75)(76)(77)(78)(79). NGS and bioinformatic strategies have been developed and applied to tumour tissue, which have allowed both a measure of heterogeneity and the generation of phylogenetic models which provide a picture of the inferred development and branched evolution of the tumour (78,(80)(81)(82).…”