Khan Mohammad Aslam, Srivastava Sanjeev K, Bhardwaj Arun, Singh Seema, Arora Sumit, Zubair Haseeb, Carter James E, Singh Ajay P
Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Oncotarget. 2015 Nov 17;6(36):39140-50. doi: 10.18632/oncotarget.3784.
Pancreatic tumor microenvironment (TME) is characterized by poor tumor-vasculature and extensive desmoplasia that together contribute to poor response to chemotherapy. It was recently shown that targeting of TME to inhibit desmoplasiatic reaction in a preclinical model resulted in increased microvessel-density and intratumoral drug concentration, leading to improved therapeutic response. This approach, however, failed to generate a favorable response in clinical trial. In that regard, we have previously demonstrated a role of gemcitabine-induced CXCR4 signaling as a counter-defense mechanism, which also promoted invasiveness of pancreatic cancer (PC) cells. Here, we investigated the effect of gemcitabine on endothelial cell phenotype. Gemcitabine-treatment of human-umbilical-vein-endothelial-cells (HUVECs) did not promote the growth of HUVECs; however, it was induced when treated with conditioned media from gemcitabine-treated (Gem-CM) PC cells due to increased cell-cycle progression and apoptotic-resistance. Moreover, treatment of HUVECs with Gem-CM resulted in capillary-like structure (CLS) formation and promoted their ability to migrate and invade through extracellular-matrix. Gemcitabine-treatment of PC cells induced expression of various growth factors/cytokines, including IL-8, which exhibited greatest upregulation. Further, IL-8 depletion in Gem-CM diminished its potency to promote angiogenic phenotypes. Together, these findings suggest an indirect effect of gemcitabine on angiogenesis, which, in light of our previous observations, may hold important clinical significance.
胰腺肿瘤微环境（TME）的特征是肿瘤血管生成不良和广泛的促结缔组织增生，这共同导致了化疗反应不佳。最近有研究表明，在临床前模型中靶向TME以抑制促结缔组织增生反应可增加微血管密度和肿瘤内药物浓度，从而改善治疗反应。然而，这种方法在临床试验中未能产生良好的反应。在这方面，我们之前已经证明吉西他滨诱导的CXCR4信号传导作为一种反击防御机制，它也促进了胰腺癌细胞（PC）的侵袭性。在此，我们研究了吉西他滨对内皮细胞表型的影响。用吉西他滨处理人脐静脉内皮细胞（HUVECs）并不会促进其生长；然而，当用来自吉西他滨处理过的（Gem-CM）PC细胞的条件培养基处理时，由于细胞周期进程加快和抗凋亡能力增强，HUVECs的生长被诱导。此外，用Gem-CM处理HUVECs会导致毛细血管样结构（CLS）形成，并促进其通过细胞外基质迁移和侵袭的能力。用吉西他滨处理PC细胞会诱导包括IL-8在内的多种生长因子/细胞因子的表达，其中IL-8上调最为明显。此外，Gem-CM中IL-8的缺失降低了其促进血管生成表型的能力。总之，这些发现表明吉西他滨对血管生成具有间接作用，鉴于我们之前的观察结果，这可能具有重要的临床意义。
