Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Abstract

A major challenge in treating cancer is posed by intratumor heterogeneity, with different sub-populations of cancer cells within the same tumor exhibiting therapy resistance through different biological processes. These include therapy-induced dormancy (durable proliferation arrest through, e.g., polyploidy, multinucleation, or senescence), apoptosis reversal (anastasis), and cell fusion. Unfortunately, such responses are often overlooked or misinterpreted as “death” in commonly used preclinical assays, including the in vitro colony-forming assay and multiwell plate “viability” or “cytotoxicity” assays. Although these assays predominantly determine the ability of a test agent to convert dangerous (proliferating) cancer cells to potentially even more dangerous (dormant) cancer cells, the results are often assumed to reflect loss of cancer cell viability (death). In this article we briefly discuss the dark sides of dormancy, apoptosis, and cell fusion in cancer therapy, and underscore the danger of relying on short-term preclinical assays that generate population-based data averaged over a large number of cells. Unveiling the molecular events that underlie intratumor heterogeneity together with more appropriate experimental design and data interpretation will hopefully lead to clinically relevant strategies for treating recurrent/metastatic disease, which remains a major global health issue despite extensive research over the past half century.

Terminalia bentzoë, a Mascarene Endemic Plant, Inhibits Human Hepatocellular Carcinoma Cells Growth In Vitro via G0/G1 Phase Cell Cycle Arrest

“…Thus, while investigating the potential anticancer effect of extracts, it is warranted to also evaluate their long-term effect on the replicative ability of the cancer cell line. The colony formation assay is a simple and useful in vitro model, considered as the gold standard to predict the long-term sensitivity of cancer cell response to therapeutics treatment [ 48 , 50 ]. In this vein, the current study evidenced the ability of T. bentzoë to impede the replicative potential of HepG2 cells ( Figure 1 ).…”

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

“…In reality, these cells are anything but static. Indeed, they exhibit considerable ongoing metabolic activity related in part to the evolution of polyploidy/senescence and subsequent depolyploidization, which can eventually lead to the emergence of para-diploid progenitor cells through a variety of mechanisms; these normal-sized progeny are highly proliferative and are variously associated with the induction of epithelial to mesenchymal transition (EMT) and acquisition of stem-cell markers [85][86][87][88]93,95,[99][100][101][102][103][104].…”

“Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres

“…The mechanisms of this MS-aided cancer resistance, which paradoxically integrates the features of cellular senescence with reprogramming, are poorly understood [8,[17][18][19][20][21][22][23][24][25][26][27][28][29]. The paracrine tumorand resistance-stimulating effects of the secretome of senescing cells are of interest [30] but the role of polyploidy as the third component of the paradoxical senescence-self-renewal duality of the chemoresistance is not sufficiently understood [8,26,[31][32][33][34].…”