Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front
Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front
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DOI：
10.1007/s00432-022-04554-5
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发表时间：
2023-01
影响因子：
3.6
通讯作者：
Shu-ke Fei;K. Ohuchida;S. Kibe;Zilong Yan;C. Iwamoto;T. Shinkawa;Bo Zhang;Jun Kawata;Toshiya Abe;Noboru Ideno;Naoki Ikenaga;Kohei Nakata;Y. Oda;Masafumi Nakamura
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文献类型：
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作者：
Shu-ke Fei;K. Ohuchida;S. Kibe;Zilong Yan;C. Iwamoto;T. Shinkawa;Bo Zhang;Jun Kawata;Toshiya Abe;Noboru Ideno;Naoki Ikenaga;Kohei Nakata;Y. Oda;Masafumi Nakamura
目的探讨血管生成在侵袭性前胰腺导管腺癌（PDAC）癌相关性腺泡-导管化生（CA-ADM）病变中的作用及其可能机制。方法对128例PDAC患者和36只LSL-KrasG 12 D/+; LSL-Trp 53 R172 H/+; Pdx-1-Cre小鼠的组织标本进行分析。采用HE染色、抗CK 19和抗淀粉酶免疫组化检测CA ADM病变的存在，抗CD 34和抗CD 31检测微血管密度（MVD），抗CD 68、抗CD 163、抗iNOS和抗MMP 9检测免疫微环境。采用多重免疫组化方法检测巨噬细胞表面MMP 9和CD 68的共表达。我们研究了临床结果和其他临床病理因素，以确定高水平的MVD的CA-ADM生存和肝转移的意义。我们进行管形成试验，以评估巨噬细胞对血管生成能力的影响，在vitro.ResultsAngiogenesis显着丰富的CA-ADM病变相比，在PDAC病变在人类和小鼠组织。CA-ADM病灶中高水平的MVD是预后不良（P= 0.0047）和肝转移复发（P= 0.0027）的独立预测因子。CD 68和CD 163阳性的巨噬细胞在CA-ADM病变中比在PDAC中检测到更多。CD 68阳性巨噬细胞百分比与MVD呈正相关。多重免疫组化显示，MMP 9表达于CA-ADM病变的CD 68阳性巨噬细胞。CA-ADM病变中巨噬细胞百分比与MMP 9表达呈正相关，MMP 9表达与微血管密度呈正相关。结论CA-ADM相关的血管生成是PDAC预后不良的一个有前景的预测指标，可能为PDAC提供一个有吸引力的治疗靶点。
PurposeThis 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.MethodsTissue samples from 128 patients with PDAC and 36 LSL-KrasG12D/+; LSL-Trp53R172H/+; 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.ResultsAngiogenesis 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.ConclusionCA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.