Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice

Abstract

Cancer development, progression, and metastasis are highly dependent on angiogenesis. The use of antiangiogenic drugs has been proposed as a novel strategy to interfere with tumor growth, but cancer cells respond by developing strategies to escape these treatments. In particular, animal models show that antiangiogenic drugs currently used in clinical settings reduce tumor tissue oxygenation and trigger molecular events that foster cancer resistance to therapy. Here, we show that semaphorin 3A (Sema3A) expression overcomes the proinvasive and prometastatic resistance observed upon angiogenesis reduction by the small-molecule tyrosine inhibitor sunitinib in both pancreatic neuroendocrine tumors (PNETs) in RIP-Tag2 mice and cervical carcinomas in HPV16/E 2 mice. By improving cancer tissue oxygenation and extending the normalization window, Sema3A counteracted sunitinib-induced activation of HIF-1α, Met tyrosine kinase receptor, epithelial-mesenchymal transition (EMT), and other hypoxia-dependent signaling pathways. Sema3A also reduced tumor hypoxia and halted cancer dissemination induced by DC101, a specific inhibitor of the VEGF pathway. As a result, reexpressing Sema3A in cancer cells converts metastatic PNETs and cervical carcinomas into benign lesions. We therefore suggest that this strategy could be developed to safely harnesses the therapeutic potential of the antiangiogenic treatment.

Chemotherapy Counteracts Metastatic Dissemination Induced by Antiangiogenic Treatment in Mice

“…Effect of sunitinib on survival ( ÃÃÃÃ , P < 0.0001; right). B, animals (10 per group) were killed with a median primary tumor of 2 Â 10 5 PC (tumor weight $1 g) on different days (median vehicle 19 (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26); sunitinib 32 (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), and lung metastases were assessed by BLI (mean AE SEM). Primary tumor (PC; left); lung metastatic burden (PC; right) at scheduled death (mean AE SEM; Ã , P < 0.05).…”

“…In some studies, antiangiogenic therapy was extremely effective on the primary tumor and metastasis, improving survival (13)(14)(15). However, surprisingly, recent studies reported that treatment of tumor-bearing mice, mainly with anti-VEGF/VEGFR-related compounds, increased tumor invasiveness and metastasis (16)(17)(18)(19)(20)(21)(22). Clinical data on the effect of antiangiogenesis in general, or anti-VEGF therapy, on malignant progression are lacking and widely debated.…”

Combinatorial treatment with carboxyamidotriazole- orotate and temozolomide in sc-implanted human LOX IMVI melanoma xenografts

“…Resistance to anti-VEGF therapy develops by activation of alternate proangiogenic pathways, likely in response to increased tumor tissue hypoxia. In preclinical studies, when angiogenesis is impaired, tumor mass shrinks initially, followed by enhanced tumor invasiveness and metastasis [14] .…”

Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor

“…8). These results pointed out that the enhanced antitumor activity observed for the CKAAKNfunctionalized squalene-gemcitabine nanoparticles reflects by the multiple ability of (i) targeting both tumor and vessel cells, (ii) inhibiting tumor growth and angiogenesis and (iii) normalizing the vasculature [51,52] (Fig. 9).…”

“…RIP-Tag2 mice offer the advantage of both a spontaneous tumor development through multistage tumorigenesis and a well-documented angiogenic switching, in parallel to cancer progression. This well-characterized mouse model represents a suitable and highly reproducible platform to perform pre-clinical trials to test the effects of and anti-tumor and anti-angiogenic drug [28,[48][49][50][51][52]. In this work we used RIP-Tag2 mice as proof-of-concept model to assess the ability of SQdFdC/SQCKAAKN NPs to impair tumor angiogenesis and, at the same time, to regress the growth of established cancers, Twelve week-old tumor-bearing RIP-Tag2 mice were injected intravenously (days 0, 3, 7 and 11) with either dFdC (15 mg/kg), SQdFdC NPs (15 mg/kg eq.…”