Clonal cooperativity in heterogenous cancers

Abstract

Tumor heterogeneity is a major obstacle to the development of effective therapies and is thus an important focus of cancer research. Genetic and epigenetic alterations, as well as altered tumor microenvironments, result in tumors made up of diverse subclones with different genetic and phenotypic characteristics. Intratumor heterogeneity enables competition, but also supports clonal cooperation via cell-cell contact or secretion of factors, resulting in enhanced tumor progression. Here, we summarize recent findings related to interclonal interactions within a tumor and the therapeutic implications of such interactions, with an emphasis on how different subclones collaborate with each other to promote proliferation, metastasis and therapy-resistance. Furthermore, we propose that disruption of clonal cooperation by targeting key factors (such as Wnt and Hedgehog, amongst others) can be an alternative approach to improving clinical outcomes.

Keywords: Clonal cooperativity; Epithelial to mesenchymal transition; Metastasis; Tumor heterogeneity.

Fig. 1. Mechanisms of metastasis of heterogeneous tumors

(A) Active Metastasis- Heterogeneous tumors contain a small percentage of innately aggressive subclones that secrete exosomes and/or release paracrine factors to enhance the aggressive properties of nearby cells. Aggressive and “transformed” subclones then actively perform the various steps of metastasis together. (B) Alternatively, innately aggressive subclones within the heterogeneous tumor remodel the tumor microenvironment, without acting directly on neighboring tumor cells. These microenvironmental alterations, such as degradation of the ECM, pave the path for innately “non-aggressive” tumor subclones to passively escape the primary tumor site and to enter the bloodstream (intravasate) and eventually metastasize. These two models for metastasis are not mutually exclusive and allow for overall increase in metastatic incidence of heterogeneous primary tumors.

Fig. 2. Therapy resistance in heterogeneous tumors

Treatment of heterogeneous tumors with targeted therapies leads to the elimination of therapy-sensitive subclones, leaving behind intrinsically drug-resistant as well as death-resistant subclones. Drug-resistant subclones, which represent the “early” resistant tumor cell subpopulations, will then repopulate the majority of the tumor. Continual treatment challenges or stochastic events can cause de novo mutations in the death-resistant subclones, rendering them therapy-resistant and allowing them to occupy the tumor as “late” resistant subpopulations.