SUMMARY We report a paracrine effect whereby endothelial cells (ECs) promote the cancer stem cell (CSC) phenotype of human colorectal cancer (CRC) cells. We showed that, without direct cell-cell contact, ECs secrete factors that promoted the CSC phenotype in CRC cells via Notch activation. In human CRC specimens, CD133 and Notch intracellular domain-positive cells co-localized with CRC cells in perivascular regions. An EC-derived, soluble form of Jagged-1, via ADAM17 proteolytic activity, led to Notch activation in CRC cells in a paracrine manner; these effects were blocked by immunodepletion of Jagged-1 in EC conditioned medium or blockade of ADAM17 activity. ECs play an active role in promoting Notch signaling and the CSC phenotype by secreting soluble Jagged-1.
Altered metabolism in cancer cells is suspected to contribute to chemoresistance but the precise mechanisms are unclear. Here we show that intracellular ATP levels are a core determinant in the development of acquired cross-drug resistance of human colon cancer cells that harbor different genetic backgrounds. Drug-resistant cells were characterized by defective mitochondrial ATP production, elevated aerobic glycolysis, higher absolute levels of intracellular ATP and enhanced HIF-1α-mediated signaling. Interestingly, direct delivery of ATP into cross-chemoresistant cells destabilized HIF-1α and inhibited glycolysis. Thus, drug-resistant cells exhibit a greater “ATP debt” defined as the extra amount of ATP needed to maintain homeostasis of survival pathways under genotoxic stress. Direct delivery of ATP was sufficient to render drug-sensitive cells drug resistant. Conversely, depleting ATP by cell treatment with an inhibitor of glycolysis, 3-bromopyruvate, was sufficient to sensitize cells cross-resistant to multiple chemotherapeutic drugs. In revealing intracellular ATP levels are a core determinant of chemoresistance in colon cancer cells, our findings may offer a foundation for new improvements to colon cancer treatment.
Epithelial–mesenchymal transition (EMT) is a critical process providing tumor cells with the ability to migrate and escape from the primary tumor and metastasize to distant sites. Recently, EMT was shown to be associated with the cancer stem cell (CSC) phenotype in breast cancer. Snail is a transcription factor that mediates EMT in a number of tumor types, including colorectal cancer (CRC). Our study was done to determine the role of Snail in mediating EMT and CSC function in CRC. Human CRC specimens were stained for Snail expression, and human CRC cell lines were transduced with a retroviral Snail construct or vector control. Cell proliferation and chemosensitivity to oxaliplatin of the infected cells were determined by the MTT (colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Migration and invasion were determined in vitro using modified Boyden chamber assays. EMT and putative CSC markers were analyzed using Western blotting. Intravenous injection of tumor cells was done to evaluate their metastatic potential in mice. Snail was overexpressed in human CRC surgical specimens. This overexpression induced EMT and a CSC-like phenotype in human CRC cells and enhanced cell migration and invasion (P < 0.002 vs. control). Snail overexpression also led to an increase in metastasis formation in vivo (P < 0.002 vs. control). Furthermore, the Snail-overexpressing CRC cells were more chemoresistant to oxaliplatin than control cells. Increased Snail expression induces EMT and the CSC-like phenotype in CRC cells, which enhance cancer cell invasion and chemoresistance. Thus, Snail is a potential therapeutic target in metastatic CRC.
Importance Hyperthermic intraperitoneal chemotherapy (HIPEC) has been employed within various multimodality strategies for the prevention and treatment of gastric cancer peritoneal carcinomatosis. Objective To systematically evaluate the role of HIPEC in gastric cancer and clarify its effectiveness at different stages of peritoneal disease progression. Data Sources Medline and Embase databases between January 1, 1985, and June 1, 2016. Study Selection Randomized control trials (RTC) and high-quality nonrandomized control trials (NRCTs) selected on a validated tool (Methodological Index for Nonrandomized Studies) comparing HIPEC and standard oncological management for the treatment of advanced stage gastric cancer with and without peritoneal carcinomatosis were considered. Data Extraction and Synthesis A random-effects network meta-analysis. Main Outcomes and Measures The primary outcomes were overall survival and disease recurrence. Secondary outcomes were overall complications, type of complications, and sites of recurrence. Results A total of 11 RCTs and 21 NRCTs (2520 patients) were included. For patients without the presence of peritoneal carcinomatosis (PC), the overall survival rates between the HIPEC and control groups at 3 or 5 years resulted in favor of the HIPEC group (RR=0.82, P=0.01). No difference in the 3-year overall survival (RR=0.99, P=0.85) in but a prolonged median survival of 4 months in favor of the HIPEC group (WMD=4.04, P<0.001) was seen in patients with PC. HIPEC was associated with significantly higher risk of complications for both patients with PC (RR=2.15, P<0.01) and without (RR=2.17, P<0.01). This increased risk in the HIPEC group was related to systemic drugs toxicity. Anastomotic leakage rates were found to be similar between groups. Conclusions and Relevance Our study demonstrates a survival advantage of the use of HIPEC as a prophylactic strategy and suggests that patients whose disease burden is limited to positive cytology and limited nodal involvement may benefit the most from HIPEC. For patients with extensive carcinomatosis, the completeness of cytoreductive surgery is a critical prognostic factor for survival. Future RCTs should better define patient selection criteria.
Background & Aims Metastatic gastrointestinal neuroendocrine tumors (NETs) are frequently refractory to chemotherapy. Chemoresistance in various malignancies has been attributed to cancer stem cells (CSCs). We sought to identify gastrointestinal neuroendocrine CSCs (N-CSCs) in surgical specimens and a NET cell line and to characterize novel N-CSC therapeutic targets. Methods Human gastrointestinal NETs were evaluated for CSCs using the Aldefluor assay. In vitro sphere-forming assay was performed on primary NET cells. CNDT2.5, a human midgut carcinoid cell line, was used for in vitro (sphere-formation) and in vivo (tumorigenicity assays) CSC studies. N-CSC protein expression was characterized using Western blotting. In vivo, systemic siRNA administration targeted Src. Results Using the Aldefluor assay, aldehyde dehydrogenase–positive (ALDH+) cells comprised 5.8% ± 1.4% (mean ± SEM) of cells from 19 patient samples. Though many primary cell lines failed to grow, CNDT96 ALDH+ cells formed spheres in anchorage-independent conditions, whereas ALDH− cells did not. CNDT2.5 ALDH+ cells formed spheres, whereas ALDH− cells did not. In vivo, ALDH+ CNDT2.5 cells generated more tumors, with shorter latency than ALDH− or sham-sorted cells. Compared with non-CSCs, ALDH+ cells demonstrated increased expression of activated Src, Erk, Akt, and mTOR. In vivo, anti-Src siRNA treatment of ALDH+ tumors reduced tumor mass by 91%. Conclusions CSCs are present in neuroendocrine tumors (NETs), demonstrated by in vitro sphere-formation and in vivo tumorigenicity assays. Src was activated in N-CSCs and represents a potential therapeutic target in gastrointestinal NETs.
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