SHH/PDGF-AA/NRP1介导肿瘤-间质交互作用影响胰腺癌恶性潜能的实验研究

Pancreatic cancer is one kind of malignant tumor which contains abundant stroma. Cancer associated fibroblast (CAF) is the main and most important content of stroma. Tumor cells and stoma interact closely with each other in pancreatic cancer. Briefly, pancreatic cancer cells can activate CAF and in turn, many cytokines and proteins secreted by CAF also can act on pancreatic cancer cells and promote their malignant phenotypes. Our previous studies indicate that 1) CAF regulates many malignant phenotypes of pancreatic cancer, such as invasion, metastasis, immune activation, angiogenesis, and chemoresistance; 2) Sonic hedgehog (SHH) is a crucial signal pathway in the microenvironment of pancreatic cancer which can activate CAF; 3) Neuropilin-1 (NRP1) is a key regulator in pancreatic cancer which is associated with SHH; 4) SHH/PDGF-AA/NRP1 axis exists in the interaction effect of tumor and stroma which contributes to the malignancy of pancreatic cancer. In the present study, we will further confirm the internal regulating effects of SHH/PDGF-AA/NRP1 axis, explore its role in the malignant phenotypes of pancreatic cancer, interfere the key link and inhibit the malignant biological behavior, and try to offer a new idea to improve the poor prognosis of pancreatic cancer.

胰腺癌是一种富含间质的恶性肿瘤，癌相关成纤维细胞CAF是间质中最主要也是最重要的细胞成分。胰腺癌细胞和间质CAF存在重要的相互调控作用。胰腺癌细胞可以导致CAF的激活，反过来CAF分泌的诸多细胞因子等也可以影响胰腺癌的恶性生物学行为。我们前期研究中证实：①CAF可以影响胰腺癌侵袭转移、免疫激活、血管生成和耐药等多种恶性表型；②音猬因子SHH是胰腺癌间质微环境中的关键信号通路，可以激活调控CAF；③神经纤毛蛋白NRP1是胰腺癌恶性生物学特性的重要调控分子，与SHH存在潜在调控关系；④胰腺癌中存在“SHH/PDGF-AA/NRP1”功能轴，通过癌细胞和间质CAF交互作用，影响其恶性表型。我们在此项研究中，希望进一步明确 “SHH/PDGF-AA/NRP1”功能轴在胰腺癌肿瘤-间质交互作用中的具体调控机制和关键环节，为干预胰腺癌间质微环境、抑制其恶性生物学行为、进而改善其不良预后提供新思路。

胰腺癌是一种富含间质的恶性肿瘤，癌相关成纤维细胞CAF是间质中最主要也是最重要的细胞成分。胰腺癌细胞和间质CAF存在重要的相互调控作用。胰腺癌细胞可以导致CAF的激活，反过来CAF分泌的诸多细胞因子等也可以影响胰腺癌的恶性生物学行为。血小板源生长因子PDGF是贮存于血小板α颗粒中的一种碱性蛋白质，以自分泌、旁分泌的方式发挥作用，相关研究表明CAF也可以分泌PDGF。我们在本研究中证实：①PDGF-AA是胰腺癌中肿瘤-间质交互作用的关键分子，存在SHH/PDGF-AA/NRP1功能轴，CAF分泌PGDF-AA，通过旁分泌影响胰腺癌恶性表型；②PDGFRA的表达和CAF呈正相关，并且和免疫浸润以及胰腺癌预后相关，可以作为未来胰腺癌治疗的靶点；③FTO直接靶向PDGFC，激活Akt信号通路，PDGFC通过自分泌调控胰腺癌的恶性生物学行为。我们关于胰腺癌中PDGF家族及其受体的一系列发现，为进一步干预胰腺癌间质微环境、抑制其恶性生物学行为、进而改善其不良预后提供了新思路。