title: Tumor and its microenvironment: a synergistic interplay.
abstract: The mutual and interdependent interaction between tumor and its microenvironment is a crucial topic in cancer research. Recently, it was reported that targeting stromal events could improve efficacies of current therapeutics and prevent metastatic spreading. Tumor microenvironment is a "complex network" of different cell types, soluble factors, signaling molecules and extracellular matrix components, which orchestrate the fate of tumor progression. As by definition, cancer stem cells (CSCs) are proposed to be the unique cell type able to maintain tumor mass and survive outside the primary tumor at metastatic sites. Being exposed to environmental stressors, including reactive oxygen species (ROS), CSCs have developed a GSH-dependent antioxidant system to improve ROS defense capability and acquire a malignant phenotype. Nevertheless, tumor progression is dependent on extracellular matrix remodeling, fibroblasts and macrophages activation in response to oxidative stress, as well as epithelial mesenchymal transition (EMT)-inducing signals and endothelial and perivascular cells recruitment. Besides providing a survival advantage by inducing de novo angiogenesis, tumor-associated vessels contribute to successful dissemination by facilitating tumor cells entry into the circulatory system and driving the formation of pre-metastatic niche. In this review, we focus on the synergistic effect of hypoxia inducible factors (HIFs) and vascular endothelial growth factors (VEGFs) in the successful outgrowth of metastasis, integrating therefore many of the emerging models and theories in the field.
authors.affiliation: University of Palermo, Department of Surgical and Oncological Sciences, Laboratory of Cellular and Molecular Pathophysiology, Via Liborio Giuffrè, 5, 90127 Palermo, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Catalano
authors.forename: Alice
authors.initials: A
authors.lastname: Turdo
authors.forename: Simone
authors.initials: S
authors.lastname: Di Franco
authors.forename: Francesco
authors.initials: F
authors.lastname: Dieli
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
mesh_terms: D000818:Animals; D002465:Cell Movement; D002470:Cell Survival; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D014411:Neoplastic Stem Cells / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010084:Oxidation-Reduction; D015398:Signal Transduction; D055153:Stem Cell Niche; D059016:Tumor Microenvironment
keywords: Angiogenesis; CAFs; CAMs; CRC; CSCs; ECM; EMT; GSH; HIF; Hypoxia; MMPs; ROS; Tumor microenvironment; VEGF; cancer stem cells; cancer-associated fibroblasts; cancer-associated macrophages; colorectal cancer; epithelial mesenchymal transition; extracellular matrix; hypoxia-inducible factor; matrix metalloproteinase; reactive oxygen species; reduced glutathione; vascular endothelial growth factor