Anti-Angiogenic Treatment in Pseudomyxoma Peritonei—Still a Strong Preclinical Rationale

Abstract

Pseudomyxoma peritonei (PMP) is a rare, slow-growing cancer characterized by progressive accumulation of intraperitoneal mucinous tumor deposits. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) cures approximately 50% of patients, but in unresectable and recurrent cases, treatment options are limited. Anti-angiogenic treatment is being explored as a potential therapeutic option. Using PMP patient samples, microvessel densities (immunostaining for CD31 and CD105) and pro-angiogenic factors were analyzed, and the proliferative response upon incubation with human umbilical cord vascular endothelial cells (HUVEC) was determined. Growth inhibition by anti-angiogenic drugs was analyzed in patient-derived xenograft models of PMP. PMP tumor tissues were found to be highly vascularized and contained key pro-angiogenic factors, in particular related to vascular endothelial growth factor (VEGF) signaling, but interestingly, high levels of fibroblast growth factor 2 were also detected. HUVEC proliferation was stimulated upon incubation with fresh tumor samples and the observed proliferation could be inhibited by VEGF pathway inhibitor bevacizumab. In xenograft models the two VEGF pathway inhibitors, bevacizumab and aflibercept, inhibited tumor growth. This work reemphasizes the importance of angiogenesis as a major driver in PMP and strengthens the preclinical rationale for continued exploration of angiogenesis inhibition in the hope of providing novel treatment to a group of patients that have few other treatment options.

Comprehensive Understanding and Evolutional Therapeutic Schemes for Pseudomyxoma Peritonei

“… 74 Compared with healthy population, higher expression of angiogenic signaling pathway protein were detected in PMP serum specimens, like VEGFA, PIGF, FGF2, and sflt1. 74 The synergistic action could promote the vascularization. Cases of apatinib treatment, trifluridine/tipiracil (TAS-102) plus bevacizumab and other protocols all have reported with prolonged PFS and improved life quality.…”

“…PMP lacks in epithelial tumor cells and riches in mucin, that character does not influence the degree of vascularization and bears slight difference with other solid neoplasms 74. Compared with healthy population, higher expression of angiogenic signaling pathway protein were detected in PMP serum specimens, like VEGFA, PIGF, FGF2, and sflt1 74. The synergistic action could promote the vascularization.…”

“…Fundamental mechanisms of antiangiogenic agents include inducing the normalization of tumor vasculature, inhibiting renascent vessels and degenerating immature parts 73. PMP lacks in epithelial tumor cells and riches in mucin, that character does not influence the degree of vascularization and bears slight difference with other solid neoplasms 74. Compared with healthy population, higher expression of angiogenic signaling pathway protein were detected in PMP serum specimens, like VEGFA, PIGF, FGF2, and sflt1 74.…”

Progress in Biological Research and Treatment of Pseudomyxoma Peritonei

“…Due to the small number of tumor cells and the large amount of mucus associated with PMP, ordinary conventional chemotherapy drugs cannot play an effective role. Relevant studies have shown that antiangiogenic therapy may be an effective treatment [155,156]. Dohan et al [156] confirmed the existence of a large number of microvessels in PMP tumor tissue through Doppler ultrasound and microangiography.…”

Novel Perspectives in Pseudomyxoma Peritonei Treatment

“…In preclinical models of PMP, tumor tissues were found to be vascularized and enriched in relevant pro-angiogenic factors associated with VEGF signaling, and inhibitors of this pathway, such as bevacizumab, were able to interfere with tumor growth in murine PMP xenografts [ 46 ]. Similarly, intraperitoneal administration of bevacizumab in an orthotopic murine model of PMP is correlated with the normalization of tumor vascularity, confirming the potential activity of anti-VEGF target therapy in PMP [ 47 ].…”