Perivascular cell‐derived extracellular vesicles stimulate colorectal cancer revascularization after withdrawal of antiangiogenic drugs

Abstract

Antiangiogenic tyrosine kinase inhibitors (AA-TKIs) have become a promising therapeutic strategy for colorectal cancer (CRC). In clinical practice, a significant proportion of cancer patients temporarily discontinue AA-TKI treatment due to recurrent toxicities, economic burden or acquired resistance. However, AA-TKI therapy withdrawal-induced tumour revascularization frequently occurs, hampering the clinical application of AA-TKIs. Here, this study demonstrates that tumour perivascular cells mediate tumour revascularization after withdrawal of AA-TKI therapy. Pharmacological inhibition and genetic ablation of perivascular cells largely attenuate the rebound effect of CRC vascularization in the AA-TKI cessation experimental settings. Mechanistically, tumour perivascular cell-derived extracellular vehicles (TPC-EVs) contain Gas6 that instigates the recruitment of endothelial progenitor cells (EPCs) for tumour revascularization via activating the Axl pathway. Gas6 silence and an Axl inhibitor markedly inhibit tumour revascularization by impairing EPC recruitment. Consequently, combination therapy of regorafenib with the Axl inhibitor improves overall survival in mice metastatic CRC model by inhibiting tumour growth. Together, these data shed new mechanistic insights into perivascular cells in off-AA-TKI-induced tumour revascularization and indicate that blocking the Axl signalling may provide an attractive anticancer approach for sustaining long-lasting angiostatic effects to improve the therapeutic outcomes of antiangiogenic drugs in CRC.

Targeting FAPα-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models

“…Cells and tumor tissues were harvested and lysed with ice-cold RIPA lysis buffer (Thermo Fisher Scientific), and the Pierce BCA Protein Assay Kit was used to measure the concentration of proteins. Western blotting was performed as described previously ( 68 ) and the antibodies are listed in Supplemental Table 9 . See complete unedited blots in the supplemental material.…”

Tumor-Derived Extracellular Vesicles Regulate Cancer Progression in the Tumor Microenvironment

“…EVs released from endothelial cells treated with vandetanib enrich VEGF, thus promoting angiogenesis and tumor growth in vivo ( Zeng et al, 2019 ). In addition, EVs released from perivascular cell trigger endothelial progenitor cells recruitment after anti-angiogenic therapy cessation, which contributes to blood vessel regrowth and rapid tumor growth ( Huang et al, 2021 ). Mechanically, Gas6-containing perivascular cell-derived EVs activate Axl signaling and subsequently promote tumor revascularization ( Huang et al, 2021 ).…”

FGF-2 signaling in nasopharyngeal carcinoma modulates pericyte-macrophage crosstalk and metastasis

“…The human TERT-immortalized fibroblast cell line was provided by George Klein at the Karolinska Institutet. Human primary pericytes were provided by Dongmei Zhang at the College of Pharmacy, Jinan University (47). Murine primary endothelial cells and primary pericytes were isolated from healthy mice by FACS.…”