Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution

Abstract

The biological complexity of cancer represents a tremendous clinical challenge, resulting in the frequent failure of current treatment protocols. In the rapidly evolving scenario of a growing tumor, anticancer treatments impose a drastic perturbation not only to cancer cells but also to the tumor microenvironment, killing a portion of the cells and inducing a massive stress response in the survivors. Consequently, treatments can act as a double-edged sword by inducing a temporary response while laying the ground for therapy resistance and subsequent disease progression. Cancer cell dormancy (or quiescence) is a central theme in tumor evolution, being tightly linked to the tumor's ability to survive cytotoxic challenges, metastasize, and resist immune-mediated attack. Accordingly, quiescent cancer cells (QCCs) have been detected in virtually all the stages of tumor development. In recent years, an increasing number of studies have focused on the characterization of quiescent/therapy resistant cancer cells, unveiling QCCs core transcriptional programs, metabolic plasticity, and mechanisms of immune escape. At the same time, our partial understanding of tumor quiescence reflects the difficulty to identify stable QCCs biomarkers/therapeutic targets and to control cancer dormancy in clinical settings. This review focuses on recent discoveries in the interrelated fields of dormancy, stemness, and therapy resistance, discussing experimental evidences in the frame of a nonlinear dynamics approach, and exploring the possibility that tumor quiescence may represent not only a peril but also a potential therapeutic resource.

Keywords: Cancer stem cells; Dormancy; Quiescence; Stemness; Therapy resistance; Tumor relapse.

Fig. 1

Different effects of cytotoxic therapies and cytostatic therapies on tumor growth and stemness. Simplified representation of the effects of cytotoxic therapies (upper panel) and cytostatic therapies (lower panel) on tumor growth (black line) and stemness (red line) during tumor evolution. CT, chemotherapy

Fig. 2

Evolution and proliferative state of therapy resistant cancer cells during tumorprogression. A Evolution of therapy resistant cells during the transition from untreated tumor (left) to residual disease (center) to progressive disease (right). Increasing tumor cell malignancy is indicated with progressively dark shades of red (lower triangle). QST, quiescent stem therapy resistant cell; PST, proliferating stem therapy-resistant cell; QT, quiescent therapy-resistant cell; PT, proliferating therapy-resistant cell. In advanced tumors (progressive disease), the majority of cells is characterized by therapy resistance and tumor-initiating potential, and stemness is not clearly definable. B Gene expression entropy increases during tumor evolution, allowing tumor cells to occupy previously latent attractors corresponding to new quiescent and proliferative states. Left: in untreated tumors, a cancer stem cell (CSC, on the top of the hill) can occupy attractors corresponding to either proliferative or quiescent phenotypes but does not have enough potential energy to occupy latent attractors. Center: anticancer therapy increases gene expression entropy, allowing CSCs to reach previously unexplored attractors and to adopt new phenotypes. During residual disease, cancer cells occupy prevalently the quiescent attractors, although few cells are also found in a proliferative state. Left: during progressive disease, most cells are found in a new attractor corresponding to an unrestrained proliferating state

Fig. 3

Cumulative effects of cytotoxic versus cytostatic therapies on tumor cells and on the tumor microenvironment (TME). Cytotoxic therapies such as standard chemotherapy induce pro-tumorigenic changes in both cancer cells and microenvironmental cells, resulting in rapid tumorprogression. Differently, cytostatic therapies (including targeted therapies and low-dose chemotherapy) induce TME alterations that are compatible with a quiescent state. Dormancy-inducing strategies acting on tumor cells and on the TME can stabilize the quiescent state and prevent degeneration toward progressive disease