Molecular Checkpoint Decisions Made by Subverted Vascular Niche Transform Indolent Tumor Cells into Chemoresistant Cancer Stem Cells

Abstract

Summary Tumor-associated endothelial cells (TECs) regulate tumor cell aggressiveness. However, the “core” mechanism by which TECs confer stem cell-like activity to indolent tumors is unknown. Here, we used in vivo murine and human tumor models to identify tumor-suppressive checkpoint role of TEC-expressed insulin growth factor (IGF) binding protein-7 (IGFBP7/angiomodulin). During tumorigenesis, IGFBP7 blocks IGF1 and inhibits expansion and engraftment of tumor stem-like cells (TSCs) expressing IGF1-receptor (IGF1R). However, chemotherapy triggers TECs to suppress IGFBP7, and this stimulates IGF1R+ TSCs to express FGF4, inducing a feed-forward FGFR1-ETS2 angiocrine cascade that obviates TEC IGFBP7. Thus, loss of IGFBP7 and upregulation of IGF1 activates the FGF4-FGFR1-ETS2 pathway in TECs and converts naive tumor cells to chemoresistant TSCs, thereby facilitating their engraftment and progression.

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

“…Hence, IGFBP7 could represent a common target of different signalling pathways to sustain stem cell features. In this respect, a role of IGFBP7 as inhibitor of the expansion and aggressiveness of tumour stem-like cells was recently proved in vivo (Cao et al, 2017).…”

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

“…IGF1R activation has been implicated in resistance to both chemical and radiation based therapies. Investigations in several different tumour types have revealed increased IGF activity in chemoresistant tumours and shown that IGF1R inhibition acts as a chemosensitizer (Dallas et al ., ; Eckstein et al ., ; Juan et al ., ; Ireland et al ., ; Cao et al ., ). Downstream activation of the PI3K/AKT pathway has been shown to be instrumental to the mechanism of chemoresistance in many of these studies.…”

Tumor endothelial cells accelerate tumor metastasis

“…(42) Cao et al described that TEC convert indolent tumor cells to more aggressive cells with greater tumorigenicity, extranodal invasion, and chemoresistance. (42,43) Moreover, other groups have also demonstrated that the Notch signals in EC are involved in tumor progression and stem cell phenotype. (44)(45)(46)(47) Notch activation in EC promotes tumor cell migration and metastasis along with neutrophil infiltration.…”