Normalization in tumor ecosystem: Opportunities and challenges

Current research in cancer therapy aims to exploit efficient strategies to have long-lasting effects on tumors and to reduce or even revoke the chance of recurrence. Within the tumor stroma, O₂ and nutrients are abnormally distributed between various cells (preferentially for supplying cancer cells), the immune contexture is abnormally positioned (permissive essentially for cells exhibiting tumor-promoting capacity), the fibroblast and fibrotic content is abnormally distributed (presence of both extracellular matrix [ECM] stiffening and ECM-degrading factors both for tumor-promoting purposes), and the tumor vasculature is abnormally orchestrated (for hindering drug delivery and increasing the chance of tumor metastasis). Resistance is actually an adaptive response to an imbalance in the tumor ecosystem; thus, the key consideration for effective cancer therapy is to bring back the normal status in this ecosystem so as to reach the desired durable outcome. Vascular normalization, metabolic modulation (glucose delivery in particular), balancing cellular dispersion, and balancing the pH rate and O₂ delivery within the tumor microenvironment are suggested strategies to reverse abnormality within the tumor stroma.