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.
Highlights
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
After a brief discussion on the contributions that these responses make to metastasis and therapy resistance, we will further examine the endpoints measured by multiwell plate assays to illustrate that, such assays lack specificity when performed with proliferating cultures, they may be useful for identifying agents capable of destroying dormant cancer cells (Section 7)
mitochondrial outer membrane permeabilization (MOMP) and caspase-3 activation continue to be used as molecular markers of cell death, relatively recent studies demonstrated that, under some circumstances, instead of functioning as an apoptosis executioner, active caspase-3 plays an important role in carcinogenesis, metastasis, and therapy resistance
Summary
“ . . . we have come full circle, beginning in a period when vast amounts of cancer research data yielded little insight into underlying mechanisms to a period (1980–2000) when a flurry of molecular and genetic research gave hope that cancer really could be understood through simple and logical reductionist thinking, and to our current dilemma” Activation of caspase-3, the key executioner caspase in the apoptotic cascade, has been widely used as a surrogate molecular marker of cell death (e.g., [9,10,11,12,13,14]) As mentioned above, this two-armed model of the DNA damage response—repair and survive or die through apoptosis—has led to the development of numerous short-term colorimetric/fluorometric assays that are ideal for high-throughput studies. After a brief discussion on the contributions that these responses make to metastasis and therapy resistance, we will further examine the endpoints measured by multiwell plate assays (e.g., crystal violet “cytotoxicity”) to illustrate that, such assays lack specificity when performed with proliferating cultures, they may be useful for identifying agents capable of destroying dormant cancer cells (Section 7)
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