Paracrine and Metabolic Adaptation in Cancer Progression

Dear Colleagues,

Cancer progression from low to high levels of malignancy is characterized by the step-by-step accumulation of specific oncogene mutations, suggesting the genetic evolution of cancer cells through random mutations and selection of the fittest. In fact, the erratic cancer homeostasis determines an unstable tumor microenvironment often characterized by harsh conditions, such as inflammation and hypoxia. Anticancer therapies also act as strong stressors, via cell (chemo/radiotherapies) or tissue (hormone/targeted therapy) damage. Both spontaneous and therapy-induced damage pose high selective pressure, favoring the survival of the most aggressive cells. However, it is emerging that this is only part of the issue. Indeed, sub-lethally damaged cells actively react to injury by setting up complex strategies aimed at adapting to the ever-changing tumor environment. These consist of specific, yet unclear, signaling pathways encompassing epigenetic, molecular, immune, and metabolic rewiring, that wounded cancer (but not non-cancer) tissues, together with their stroma components and recruited immune cells, orchestrate to cope with stress. Such reactions create phenotypic metastable plasticity states (for example, epithelial-to-mesenchymal transition), which go far beyond mere cell survival, rather including the acquisition of resistance, directional motility, tolerance to DNA alterations, and loss of adhesion, DNA repair, and error-free DNA synthesis functions. Such events are characterized by strong paracrine signaling and rely on the acquisition of metabolic adaptation. Notably, they precede and are responsible for, genetic evolution, promoting heterogeneity and preparing the ground for genetic selection, suggesting that adaptation and selection are cooperative rather than alternative phenomena for tumor progression. An important implication is that such adaptive processes are theoretically druggable, opening novel therapeutic options aimed at limiting the adaptation phenomena that are responsible for cancer progression.

In this Special Issue, we aim at collecting Research Articles, Review Articles, and Communications to highlight the state of the art of the issue and the possible therapeutic implications.

Prof. Dr. Lina Ghibelli
Guest Editor

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• cancer microenvironment
• metabolic reprogramming
• epigenetic reprogramming
• chronic inflammation
• genetic instability
• cancer heterogeneity
• senescence
• epithelial-to-mesenchymal transition
• paracrine signaling and homeostatic pathways
• hypoxia
• response to therapy