Abstract
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.
Highlights
Pancreatic cancer (PC) is largely an incurable malignancy and one of the deadliest cancers in the United States
Since enhanced gemcitabine accumulation at the tumor site coincided with enhanced blood vessel formation [11], we first examined the effect of gemcitabine treatment on the growth of human umbilical vein endothelial cells (HUVECs)
We examined the indirect effect of gemcitabine on endothelial cell growth by treating them with the conditioned media from vehicle (V-CM) or gemcitabine (Gem-CM) treated PC (Colo-357 and MiaPaCa) cells for 24 and 48 h
Summary
Pancreatic cancer (PC) is largely an incurable malignancy and one of the deadliest cancers in the United States. The median survival after diagnosis is ~2–8 months, and only ~6% of all patients with PC survive 5 years post-diagnosis [2]. At the time of diagnosis, most pancreatic tumors are either highly genetically advanced or have spread to distant sites leaving systemic chemotherapy as the only viable option for treatment [3]. None of the chemotherapeutic regimen (single agent or combination) has been very successful, and all provide only marginal survival benefit at the best to the PC patients [4, 5]. There remains a concern for unintended and undesired effects of chemotherapy supported by recent findings [3, 6]. It is extremely important that we develop an improved understanding of the mechanisms underlying chemoresistance of PC as well as the host response to chemotherapy that may adversely affect overall clinical outcome
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