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

Shuang Fei; Kenoki Ohuchida; Shin Kibe; Zilong Yan; Chika Iwamoto; Tomohiko Shinkawa; Bo Zhang; Jun Kawata; Toshiya Abe; Noboru Ideno; Naoki Ikenaga; Kohei Nakata; Yoshinao Oda; Masafumi Nakamura

doi:10.1007/s00432-022-04554-5

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

J Cancer Res Clin Oncol. 2023 Aug;149(9):5885-5899. doi: 10.1007/s00432-022-04554-5. Epub 2023 Jan 2.

Authors

Shuang Fei¹, Kenoki Ohuchida^{2

3}, Shin Kibe¹, Zilong Yan^{1

4}, Chika Iwamoto^{1

5}, Tomohiko Shinkawa¹, Bo Zhang¹, Jun Kawata⁶, Toshiya Abe¹, Noboru Ideno¹, Naoki Ikenaga¹, Kohei Nakata¹, Yoshinao Oda⁶, Masafumi Nakamura⁷

Affiliations

¹ Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan.
² Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. ouchida.kenoki.060@m.kyushu-u.ac.jp.
³ Cancer Center of Kyushu University Hospital, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. ouchida.kenoki.060@m.kyushu-u.ac.jp.
⁴ Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
⁵ Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Matsuyama, Japan.
⁶ Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan.
⁷ Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. nakamura.masafumi.861@m.kyushu-u.ac.jp.

PMID: 36592214
DOI: 10.1007/s00432-022-04554-5

Abstract

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.

Keywords: Angiogenesis; Cancer-associated acinar-to-ductal metaplasia; Liver metastasis; Macrophages; Pancreatic cancer; Prognosis.

MeSH terms

Animals
Carcinoma, Pancreatic Ductal* / pathology
Humans
Liver Neoplasms*
Metaplasia
Mice
Pancreatic Neoplasms* / pathology
Tumor Microenvironment

Grants and funding

JP19K22663, JP19K22664, JP22H02922, JP22K15560, JP22K16490./Japan Society for the Promotion of Science