Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front

• Published in: Journal of cancer research and clinical oncology 2023-08, Vol.149 (9), p.5885-5899
• Main Authors: Fei, Shuang, Ohuchida, Kenoki, Kibe, Shin, Yan, Zilong, Iwamoto, Chika, Shinkawa, Tomohiko, Zhang, Bo, Kawata, Jun, Abe, Toshiya, Ideno, Noboru, Ikenaga, Naoki, Nakata, Kohei, Oda, Yoshinao, Nakamura, Masafumi
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Angiogenesis; Animals; Cancer Research; Carcinoma, Pancreatic Ductal - pathology; CD163 antigen; CD34 antigen; Gelatinase B; Hematology; Humans; Internal Medicine; Invasiveness; Lesions; Liver; Liver Neoplasms; Macrophages; Medical prognosis; Medicine; Medicine & Public Health; Metaplasia; Metastases; Metastasis; Mice; Microenvironments; Nitric-oxide synthase; Oncology; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; Prognosis; Therapeutic targets; Tumor Microenvironment
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-022-04554-5

Purpose This study aimed to demonstrate the involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia (CA-ADM) lesion of invasive front pancreatic ductal adenocarcinoma (PDAC) and investigate the possible mechanism. Methods Tissue samples from 128 patients with PDAC and 36 LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx-1-Cre mice were analyzed. Immunohistochemical assay was performed using HE, anti-CK19 and anti-amylase to confirm the presence of CA-ADM lesions, using anti-CD34 and anti-CD31 to measure microvessel density (MVD), and using anti-CD68, anti-CD163, anti-iNOS, or anti-MMP9 to evaluate the immune microenvironment. We performed multiplex immunohistochemical assay to detect the co-expression of MMP9 and CD68 on macrophage. We examined clinical outcomes and other clinicopathological factors to determine the significance of high-level MVD of CA-ADM on survival and liver metastasis. We performed tube formation assay to evaluate the effect of macrophage on angiogenic capacity in vitro. Results Angiogenesis was significantly abundant in CA-ADM lesions compared with that in PDAC lesions in human and mouse tissues. High-level MVD in CA-ADM lesions was an independent predictor of poor prognosis ( P  = 0.0047) and the recurrence of liver metastasis ( P  = 0.0027). More CD68-positive and CD163-positive macrophages were detected in CA-ADM lesions than in PDAC. The percentage of CD68-positive macrophages was positively correlated with MVD in CA-ADM lesions. Multiplex-immunostaining revealed that MMP9 was expressed in CD68-positive macrophages of CA-ADM lesions. In CA-ADM lesions, the percentage of macrophages was positively correlated with MMP9 expression, which positively correlated with microvessel density. Conclusion CA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.