Figure 1.

Stromal cell types in early and late-stage tumors. (A) early tumors consist of non-aggressive quiescent fibroblasts in the Tumor microenvironment (TME). (B) Factors such as hypoxia lead to tumor inflammation and trigger environmental clues that participate in the paracrine signaling loop (cytokines, chemokines, growth factors) and angiogenic switches (VEGF, PDGF-b, FGF, and EGF) which causes stromal cell polarization or reprogramming. Together all these factors are responsible for the diversification of stromal cell types during cancer development. (C) Cytokines growth factors such as TGF-b, IL-6 released from tumor cells activate quiescent fibroblasts. (D) Activated fibroblasts further reprogram to secretory phenotypes specialized in ECM remodeling and immuno-modulation. These fibroblasts have enhanced proliferative and matrix secreting (desmoplasia) capabilities. Some of these aggressive cancer-associated fibroblasts (CAF) subtypes found in different types of cancers include antigen-presenting CAFs (apCAFs), inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs). These subtypes are explored through single-cell RNA sequencing transcriptomics and are named according to the secretory factors and roles which these phenotypes play in the TME. (E) Different types of endothelial cells found in tumor tissues: common endothelial cell types found in core or adjacent tumor areas are known as tumor endothelial cells. Apart from conventional tip and stalk cells, various subpopulations have been identified that express gene signatures related to the basement membrane breaching (triggering metastasis), immune cell recruitment, and immuno-modulation (causing immunosuppressive TME). Identifying such angiogenic candidates with activated angiogenic transcription factors and enzymes responsible for angiogenesis will be a potential source to develop anti-angiogenic strategies.