Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment

Abstract

Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapeutics owing to dense fibrotic stroma orchestrated by cancer-associated pancreatic stellate cells (CAPaSC). CAPaSC also support cancer cell growth, metastasis, and resistance to apoptosis. Currently, there is no effective therapy for PDAC that specifically targets CAPaSC. We previously reported a rationally designed protein, ProAgio, that targets integrin α v β 3 at a novel site and induces apoptosis in integrin α v β 3 -expressing cells. Because both CAPaSC and angiogenic endothelial cells express high levels of integrin α v β 3 , we aimed to analyze the effects of ProAgio in PDAC tumor. Methods Expression of integrin α v β 3 was examined in both patient tissue and cultured cells. The effects of ProAgio on CAPaSC were analyzed using an apoptosis assay kit. The effects of ProAgio in PDAC tumor were studied in 3 murine tumor models: subcutaneous xenograft, genetic engineered (Kras G12D ; p53 R172H ; Pdx1-Cre, GEM-KPC) mice, and an orthotopic KrasG12D; p53R172H; Pdx1-Cre (KPC) model. Results ProAgio induces apoptosis in CAPaSC. ProAgio treatment significantly prolonged survival of a genetically engineered mouse–KPC and orthotopic KPC mice alone or in combination with gemcitabine (Gem). ProAgio specifically induced apoptosis in CAPaSC, resorbed collagen, and opened collapsed tumor vessels without an increase in angiogenesis in PDAC tumor, enabling drug delivery into the tumor. ProAgio decreased intratumoral insulin-like growth factor 1 levels as a result of depletion of CAPaSC and consequently decreased cytidine deaminase, a Gem metabolism enzyme in cancer cells, and thereby reduced resistance to Gem-induced apoptosis. Conclusions Our study suggests that ProAgio is an effective PDAC treatment agent because it specifically depletes CAPaSC and eliminates tumor angiogenesis, thereby enhancing drug delivery and Gem efficacy in PDAC tumors.

Photodynamic Therapy for Pancreatic Ductal Adenocarcinoma

“…Integrins constitute a superfamily of 24 heterodimeric cell surface receptors, and play a vital role in transducing mechanical signals between the intracellular and extracellular components [80]. Given that integrins regulate cellular proliferation, adhesion, invasion, and cancer progression, it is not surprising that some integrins have been used as potential therapeutic targets in PDAC [81][82][83][84]. While there have been some studies that focused on the impact of PDT on integrins in different types of cancers, there have not been any studies that investigated targeting integrins with PDT in PDAC [85][86][87].…”

Overview and Future Perspectives on Tumor-Targeted Positron Emission Tomography and Fluorescence Imaging of Pancreatic Cancer in the Era of Neoadjuvant Therapy

“…From the aforementioned PDAC-associated integrins, expression and function of integrins αvβ3 and αvβ6 have been most extensively evaluated. Integrin αvβ3 is expressed on stromal and endothelial cells in ~60% of PDAC, whereas integrin αvβ6 is expressed on the epithelial cells of 80–90% of PDAC lesions [ 93 , 94 , 95 , 96 , 97 ]. Integrin αvβ3 shows low to moderate expression on normal pancreatic tissue and moderate expression in pancreatitis [ 97 ].…”

Targeting Pancreatic Ductal Adenocarcinoma (PDAC)

“…Zhi-Ren Liu's group has recently developed a tailor-made protein, ProAgio, which binds to Integrin α v β 3 -expressing cells, such as the endothelial cells of neovasculature and PSC cells, induces apoptosis and thereby inhibits angiogenesis [162,163]. A PEGylated form of the protein was first administered i.p.…”

“…Remarkably, this did not result in facilitation of metastases, apparently because IGF-1 levels were reduced. Survival of the mice was drastically improved [162].…”