Abstract
Tumor initiation at either primary or metastatic sites is an inefficient process in which tumor cells must fulfill a series of conditions. One critical condition involves the ability of individual tumor-initiating cells to overcome 'isolation stress', enabling them to survive within harsh isolating microenvironments that can feature nutrient stress, hypoxia, oxidative stress and the absence of a proper extracellular matrix (ECM). In response to isolation stress, tumor cells can exploit various adaptive strategies to develop stress tolerance and gain stemness features. In this Opinion, we discuss how strategies such as the induction of certain cell surface receptors and deposition of ECM proteins enable tumor cells to endure isolation stress, thereby gaining tumor-initiating potential. As examples, we highlight recent findings from our group demonstrating how exposure of tumor cells to isolation stress upregulates the G-protein-coupled receptor lysophosphatidic acid receptor 4 (LPAR4), its downstream target fibronectin and two fibronectin-binding integrins, α5β1 and αvβ3. These responses create a fibronectin-rich niche for tumor cells, ultimately driving stress tolerance, cancer stemness and tumor initiation. We suggest that approaches to prevent cancer cells from adapting to stress by suppressing LPAR4 induction, blocking its downstream signaling or disrupting fibronectin-integrin interactions hold promise as potential strategies for cancer treatment.