Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
Cancer Res. 2020 Oct 1;80(19):4058-4070. doi: 10.1158/0008-5472.CAN-19-2745. Epub 2020 Jun 30.
Pancreatic ductal adenocarcinoma (PDAC) features abundant stromal cells with an excessive extracellular matrix (ECM), termed the desmoplastic reaction. CXCR4 is a cytokine receptor for stromal cell-derived factor-1 (CXCL12) expressed in PDAC, but its roles in PDAC and the characteristic desmoplastic reaction remain unclear. Here, we generated a mouse model of PDAC with conditional knockout of Cxcr4 (KPC-Cxcr4-KO) by crossing Cxcr4 flox mice with Pdx1-Cre;KrasLSL-G12D/+;Trp53LSL-R172H/+ (KPC-Cxcr4-WT) mice to assess the development of pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancers. Tumor cell characteristics of those two types were analyzed . In addition, CXCR4 expression in human pancreatic cancer specimens was evaluated by IHC staining. In KPC-Cxcr4-KO mice, the number and pathologic grade of PanIN lesions were reduced, but the frequency of pancreatic cancers did not differ from that in KPC-Cxcr4-WT mice. The pancreatic tumor phenotype in KPC-Cxcr4-KO mice was significantly larger and undifferentiated, characterized by abundant vimentin-expressing cancer cells, significantly fewer fibroblasts, and markedly less deposition of ECM. , KPC-Cxcr4-KO tumor cells exhibited higher proliferative and migratory activity than KPC-Cxcr4-WT tumor cells. Myofibroblasts induced invasion activity in KPC-Cxcr4-WT tumor cells, showing an epithelial-mesenchymal interaction, whereas KPC-Cxcr4-KO tumor cells were unaffected by myofibroblasts, suggesting their unique nature. In human pancreatic cancer, undifferentiated carcinoma did not express CXCR4 and exhibited histologic and IHC features similar to those in KPC-Cxcr4-KO mice. In summary, the CXCL12/CXCR4 axis may play an important role in the desmoplastic reaction in PDAC, and loss of CXCR4 induces phenotype changes in undifferentiated carcinoma without a desmoplastic reaction. SIGNIFICANCE: The current study uncovers CXCR4 as a key regulator of desmoplastic reaction in PDAC and opens the way for new therapeutic approaches to overcome the chemoresistance in patients with PDAC.
胰腺导管腺癌（PDAC）的特征是富含间质细胞和大量细胞外基质（ECM），称为纤维母细胞反应。趋化因子受体 4（CXCR4）是基质细胞衍生因子 1（CXCL12）的细胞因子受体，在 PDAC 中表达，但它在 PDAC 中的作用和特征性纤维母细胞反应仍不清楚。在这里，我们通过将 Cxcr4 flox 小鼠与 Pdx1-Cre；KrasLSL-G12D/+；Trp53LSL-R172H/+（KPC-Cxcr4-WT）小鼠杂交，生成了条件敲除 Cxcr4 的 PDAC 小鼠模型（KPC-Cxcr4-KO），以评估胰腺上皮内瘤变（PanIN）和胰腺癌症的发展。分析了这两种类型的肿瘤细胞特征。此外，通过免疫组织化学染色评估了人胰腺癌细胞标本中 CXCR4 的表达。在 KPC-Cxcr4-KO 小鼠中，PanIN 病变的数量和病理分级减少，但胰腺癌的发生频率与 KPC-Cxcr4-WT 小鼠无差异。KPC-Cxcr4-KO 小鼠的胰腺肿瘤表型明显更大且未分化，其特征是大量表达波形蛋白的癌细胞、显著较少的成纤维细胞和明显较少的 ECM 沉积。此外，KPC-Cxcr4-KO 肿瘤细胞的增殖和迁移活性高于 KPC-Cxcr4-WT 肿瘤细胞。肌成纤维细胞诱导 KPC-Cxcr4-WT 肿瘤细胞的侵袭活性，表现出上皮-间充质相互作用，而 KPC-Cxcr4-KO 肿瘤细胞不受肌成纤维细胞的影响，表明其具有独特的性质。在人胰腺癌细胞中，未分化癌不表达 CXCR4，其组织学和免疫组织化学特征与 KPC-Cxcr4-KO 小鼠相似。总之，CXCL12/CXCR4 轴可能在 PDAC 的纤维母细胞反应中发挥重要作用，而 CXCR4 的缺失诱导无纤维母细胞反应的未分化癌的表型改变。意义：本研究揭示了 CXCR4 是 PDAC 纤维母细胞反应的关键调节因子，并为克服 PDAC 患者的化疗耐药性开辟了新的治疗方法。
