Fig. 1

Molecular alterations found in the tumor microenvironment (ME) and the role of stromal cells in therapy resistance and disease recurrence. Upper panel: different steps comprised between initial therapeutic approach and tumor recurrence. 1 Tumor and ME cells at the beginning of selective drug therapy. 2 The selective pressure imposed by treatment contributes to the acquisition of secondary tumor mutations and genetic alterations in ME cells, which in turn affect tumor cells. ME alterations are represented in the CAF cell shown in the lower panel. Most of these alterations are associated with the loss of expression of tumor suppressor genes, such as PTEN and APC, which leads to increased tumor survival and proliferation. Furthermore, the loss of TP53 expression observed in CAF increases ENOS activity, which culminates in an elevation of reactive nitrogen species (RNS) and the consequent transformation of the epithelial tissue surrounding the tumor. Moreover, the higher expression of growth factors (e.g., VEGF, PDGF and HGF) contributes to tumor growth and invasion, while TGF-β down-regulation decreases the expression of CDK inhibitors (p15, p16 and p21) in tumor cells, leading to tumor proliferation and survival. On the other hand, TGF-β up-regulation increases the expression of genes related with extracellular matrix (ECM) remodeling (Col I, Col III, MMP 9, MMP 11 and MMP23) which directly contribute to tumor progression. 3 ME cellular alterations, in addition to the recruitment of immune cells, and the increase in ME inflammation create a protective niche that results in therapy resistance. 4 The final outcome: tumor re-growth and disease recurrence