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.

The Immune Privilege of Cancer Stem Cells: A Key to Understanding Tumor Immune Escape and Therapy Failure

“…Indeed, CSC niches are made of non-cancerous stromal cells (i.e., cancer-associated fibroblasts (CAFs), endothelial cells, mesenchymal stem cells) and cancerous non-stem cells that by providing cues in the form of secreted factors (i.e., cytokines, extracellular vesicles and extracellular matrix (ECM) components) and complex interplays protect CSC exclusive abilities to self-renew, progress and disseminate in secondary sites [ 53 ]. Of note, the constant and evolving interplay with microenvironmental players, endows cancer (stem) cells with the ability to corrupt infiltrating immune cells, thus guaranteeing their survival and progression into overt disease [ 54 ]. Indeed, the bidirectional interaction of cancer cells with the microenvironment is of vital importance in developing immune escaping variants as a natural consequence of spatial and nutrient competition and evolutionary forces, which finally fuel tumor heterogeneity [ 55 ].…”

A retrospective study on prophylactic regional lymphadenectomy versus nodal observation only in the management of dogs with stage I, completely resected, low-grade cutaneous mast cell tumors

“…More speculatively, it may be hypothesized that quiescent neoplastic cells residing in the regional LN may at some point regain the cell cycles and relocate at distant cutaneous sites, giving rise to overt disease. 18 In the current series, it was not investigated whether the new cMCTs were of the same histological grade and mutational status of the primary tumor, impeding any further comment.…”

Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions

“…At the same time, cancer cells maintain a high metabolic plasticity [ 131 ] in order to cope with fluctuations in nutrients and oxygen levels during cancer progression, resulting in the survival of the fittest. Additionally, in multiple tumors, including breast and colon cancer, a fraction of quiescent cells presumably maintaining an oxidative phosphorylation (OXPHOS)-based metabolism [ 132 ] is responsible for resistance and relapse to therapy, as well as immune escape [ 133 ].…”