Tuning Cancer Fate: Tumor Microenvironment's Role in Cancer Stem Cell Quiescence and Reawakening

Abstract

Cancer cell dormancy is a common feature of human tumors and represents a major clinical barrier to the long-term efficacy of anticancer therapies. Dormant cancer cells, either in primary tumors or disseminated in secondary organs, may reawaken and relapse into a more aggressive disease. The mechanisms underpinning dormancy entry and exit strongly resemble those governing cancer cell stemness and include intrinsic and contextual cues. Cellular and molecular components of the tumor microenvironment persistently interact with cancer cells. This dialog is highly dynamic, as it evolves over time and space, strongly cooperates with intrinsic cell nets, and governs cancer cell features (like quiescence and stemness) and fate (survival and outgrowth). Therefore, there is a need for deeper insight into the biology of dormant cancer (stem) cells and the mechanisms regulating the equilibrium quiescence-versus-proliferation are vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. Here, we review and discuss microenvironmental regulations of cancer dormancy and its parallels with cancer stemness, and offer insights into the therapeutic strategies adopted to prevent a lethal recurrence, by either eradicating resident dormant cancer (stem) cells or maintaining them in a dormant state.

Keywords: cancer stem cells (CSC); disseminated cancer cells (DCC); dormancy; immune escape; immunoediting of cancer; reawakening; tumor evolution; tumor microenvironment.

Figure 1

Principles and temporal course of cancer dormancy. Along with primary tumor development, a state of dormancy (red line) allows the survival of microscopic bulk cancer cells. The progressive evolution of the tumor, accumulating genetic and epigenetic changes, and its microenvironment, molding immune, and angiogenic contextures, eventually lead to tumor outgrowth (blue line). At this time, early disseminated cancer cells may develop and home to metastatic sites (mainly bone marrow, lungs, lymph nodes, and brain). Following treatment (either surgery or therapy or both) leading to tumor regression, resistant cells may persist latent (red line) and constitute an undetectable minimal residual disease. At this time, late disseminated cancer cells may develop and join early counterparts at secondary organs. After a time lag, which can last from a few months to many years, these disseminated cells may overgrow and give rise to metastatic clinical relapse (blue line). Dormancy might be due to solitary cells entered into a G₀ phase of cell cycle arrest (cancer cell dormancy) or to the equilibrium between the rate of proliferation and apoptosis (tumor mass dormancy) mainly influenced by angiogenic and immunological cues.

Figure 2

Microenvironmental patterns tuning cancer dormancy, reawakening, and stemness. A schematic model showing the plethora of microenvironmental cues, encompassing the cellular, molecular, and physical factors, that converge to induce either stress-related or mitogenic signals to cancer cells. The bulk of cancer cells, encompassing disseminated and stem cells, in the face of contextual signals, either enter or exit dormancy.