Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications.
Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications.
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DOI：
10.18632/oncotarget.3784
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发表时间：
2015-11-17
期刊：
影响因子：
--
通讯作者：
Singh AP
中科院分区：
文献类型：
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作者：
Khan MA;Srivastava SK;Bhardwaj A;Singh S;Arora S;Zubair H;Carter JE;Singh AP
胰腺肿瘤微环境(TME)的特点是肿瘤血管发育不良和广泛的结缔组织增生，这些共同导致对化疗的不良反应。最近有研究表明，在临床前模型中，靶向TME以抑制促结缔组织反应可以增加微血管密度和肿瘤内药物浓度，从而改善治疗效果。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，我们之前已经证明了吉西他滨诱导的CXCR4信号作为一种反防御机制的作用，这也促进了胰腺癌(PC)细胞的侵袭性。在这里，我们研究了吉西他滨对内皮细胞表型的影响。吉西他滨处理的人脐静脉内皮细胞(HUVECs)不能促进HUVECs的生长，但吉西他滨处理的PC细胞的条件培养液(Gem-CM)可以诱导HUVECs的生长，这是因为吉西他滨处理的PC细胞的细胞周期和抗凋亡能力增强。此外，Gem-CM处理人脐静脉内皮细胞可形成毛细血管样结构，并促进其通过细胞外基质迁移和侵袭的能力。吉西他滨可诱导PC细胞表达多种生长因子/细胞因子，其中IL-8的表达上调幅度最大。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。综上所述，这些发现表明吉西他滨对血管生成有间接影响，根据我们之前的观察，这可能具有重要的临床意义。
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.