Microenvironment-mediated cancer dormancy: Insights from metastability theory

Abstract

Dormancy is an evolutionarily conserved protective mechanism widely observed in nature. A pathological example is found during cancer metastasis, where cancer cells disseminate from the primary tumor, home to secondary organs, and enter a growth-arrested state, which could last for decades. Recent studies have pointed toward the microenvironment being heavily involved in inducing, preserving, or ceasing this dormant state, with a strong focus on identifying specific molecular mechanisms and signaling pathways. Increasing evidence now suggests the existence of an interplay between intracellular as well as extracellular biochemical and mechanical cues in guiding such processes. Despite the inherent complexities associated with dormancy, proliferation, and growth of cancer cells and tumor tissues, viewing these phenomena from a physical perspective allows for a more global description, independent from many details of the systems. Building on the analogies between tissues and fluids and thermodynamic phase separation concepts, we classify a number of proposed mechanisms in terms of a thermodynamic metastability of the tumor with respect to growth. This can be governed by interaction with the microenvironment in the form of adherence (wetting) to a substrate or by mechanical confinement of the surrounding extracellular matrix. By drawing parallels with clinical and experimental data, we advance the notion that the local energy minima, or metastable states, emerging in the tissue droplet growth kinetics can be associated with a dormant state. Despite its simplicity, the provided framework captures several aspects associated with cancer dormancy and tumor growth.

Clinical and Biological Aspects of Disseminated Tumor Cells and Dormancy in Breast Cancer

“…The TME has been shown to be crucial for tumor dormancy initiation and maintenance in breast cancer cells ( Bakhshandeh et al, 2022 ) via paracrine/niche-related signaling [e.g., bone morphogenetic protein (BMP) 4 and 7 ( Kobayashi et al, 2011 ; Gao et al, 2012 ), TGF-β2 ( Bragado et al, 2013 ) and type 3 collagen ( Di Martino et al, 2022 )] that can maintain cancer cell dormancy in experimental models. In the BM as the most studied sanctuary for DTCs, three supporting niches have been described.…”

Exosome-Derived Non-Coding RNAs in the Tumor Microenvironment of Colorectal Cancer: Possible Functions, Mechanisms and Clinical Applications

“…Cancer progression is dependent on the capacity of tumor cells to establish a supportive TME ( 14 ). Studies have demonstrated that the microenvironment is involved in causing a condition of growth arrest in the tumor ( 15 ). At the same time, tumors fight against the normal microenvironment to overcome the anti-tumor pressure ( 15 ).…”

“…Studies have demonstrated that the microenvironment is involved in causing a condition of growth arrest in the tumor ( 15 ). At the same time, tumors fight against the normal microenvironment to overcome the anti-tumor pressure ( 15 ). While tumors communicate closely with the surrounding microenvironment, the biochemical signals in the microenvironment impact cell growth and tumorigenesis ( 16 , 17 ).…”

Alterations of Cytoskeleton Networks in Cell Fate Determination and Cancer Development

“…The interactions between the dysfunctional tissues and nutrients can then start a destructive cycle of overnutrition and oxidative stress [ 134 , 135 ]. In addition, oxidative stress also triggers tumor cell dormancy [ 136 ] and autophagy to prevent cell apoptosis [ 137 ], which promotes the survival of dormant cancer cells and increases the chances of metastatic tumor recurrence [ 138 ].…”