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Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma.

ABSTRACT: There is growing evidence that antiangiogenic therapy stimulates cancer cell invasion and metastasis. However, the underlying molecular mechanisms responsible for these changes have not been fully defined. Here, we report that anti-VEGF therapy promotes local invasion and metastasis by inducing collagen signaling in cancer cells. We show that chronic VEGF inhibition in a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDA) induces hypoxia, a less differentiated mesenchymal-like tumor cell phenotype, TGF-? expression, and collagen deposition and signaling. In addition, we show that collagen signaling is critical for protumorigenic activity of TGF-? in vitro. To further model the impact of collagen signaling in tumors, we evaluated PDA in mice lacking Sparc, a protein that reduces collagen binding to cell surface receptors. Importantly, we show that loss of Sparc increases collagen signaling and tumor progression. Together, these findings suggest that collagen actively promotes PDA spread and that enhanced disease progression associated with anti-VEGF therapy can arise from elevated extracellular matrix-mediated signaling.

SUBMITTER: Aguilera KY

PROVIDER: S-EPMC3944405 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma.

Aguilera Kristina Y KY Rivera Lee B LB Hur Hoon H Carbon Juliet G JG Toombs Jason E JE Goldstein Courtney D CD Dellinger Michael T MT Castrillon Diego H DH Brekken Rolf A RA

Cancer research 20131217 4

There is growing evidence that antiangiogenic therapy stimulates cancer cell invasion and metastasis. However, the underlying molecular mechanisms responsible for these changes have not been fully defined. Here, we report that anti-VEGF therapy promotes local invasion and metastasis by inducing collagen signaling in cancer cells. We show that chronic VEGF inhibition in a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDA) induces hypoxia, a less differentiated mesenchyma ...[more]

PMID: 24346431

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Project description:BackgroundNovel therapeutic strategies are urgently needed for patients with a delayed diagnosis of pancreatic ductal adenocarcinoma (PDAC) in order to improve their chances of survival. Recent studies have shown potent anti-neoplastic effects of curcumin and its analogues. In addition, the role of histone methyltransferases on cancer therapeutics has also been elucidated. However, the relationship between these two factors in the treatment of pancreatic cancer remains unknown. Our working hypothesis was that L48H37, a novel curcumin analog, has better efficacy in pancreatic cancer cell growth inhibition in the absence of histone-lysine N-methyltransferase 2D (KMT2D).AimTo determine the anti-cancer effects of L48H37 in PDAC, and the role of KMT2D on its therapeutic efficacy.MethodsThe viability and proliferation of primary (PANC-1 and MIA PaCa-2) and metastatic (SW1990 and ASPC-1) PDAC cell lines treated with L48H37 was determined by CCK8 and colony formation assay. Apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels, and cell cycle profile were determined by staining the cells with Annexin-V/7-AAD, JC-1, DCFH-DA, and PI respectively, as well as flow cytometric acquisition. In vitro migration was assessed by the wound healing assay. The protein and mRNA levels of relevant factors were analyzed using Western blotting, immunofluorescence and real time-quantitative PCR. The in situ expression of KMT2D in both human PDAC and paired adjacent normal tissues was determined by immunohistochemistry. In vivo tumor xenografts were established by injecting nude mice with PDAC cells. Bioinformatics analyses were also conducted using gene expression databases and TCGA.ResultsL48H37 inhibited the proliferation and induced apoptosis in SW1990 and ASPC-1 cells in a dose- and time-dependent manner, while also reducing MMP, increasing ROS levels, arresting cell cycle at the G2/M stages and activating the endoplasmic reticulum (ER) stress-associated protein kinase RNA-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/activating transcription factor 4 (ATF4)/CHOP signaling pathway. Knocking down ATF4 significantly upregulated KMT2D in PDAC cells, and also decreased L48H37-induced apoptosis. Furthermore, silencing KMT2D in L48H37-treated cells significantly augmented apoptosis and the ER stress pathway, indicating that KMT2D depletion is essential for the anti-neoplastic effects of L48H37. Administering L48H37 to mice bearing tumors derived from control or KMT2D-knockdown PDAC cells significantly decreased the tumor burden. We also identified several differentially expressed genes in PDAC cell lines expressing very low levels of KMT2D that were functionally categorized into the extrinsic apoptotic signaling pathway. The KMT2D high- and low-expressing PDAC patients from the TCGA database showed similar survival rates,but higher KMT2D expression was associated with poor tumor grade in clinical and pathological analyses.ConclusionL48H37 exerts a potent anti-cancer effect in PDAC, which is augmented by KMT2D deficiency.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is highly malignant due to its late diagnosis and early metastasis. Lung metastasis of PDAC occurs in a significant number of diagnosed patients and represents high severity of disease and poor clinical outcome. However, the molecular regulation of lung metastasis of PDAC is still not fully understood. Tumor-associated macrophages (TAMs) have recently been found to play an important role in cancer initiation, proliferation, progression, and metastasis. The proliferation, differentiation, and polarization of macrophages has been shown to be regulated by interleukin 1β (IL-1β), which is generated by NLR family pyrin domain containing 3 (NLRP3)-induced formation of inflammasome. Herein we investigated whether NLRP3 plays a role in lung metastasis of PDAC through regulation of macrophage polarization.MethodsGene profiles for NLRP3 (+/+) and NLRP3 (-/-) macrophages obtained from the Gene Expression Omnibus (GEO) public database were compared and analyzed for altered genes related to macrophage polarization. The regulation of macrophage polarization by NLRP3 was examined in a coculture system with naïve NLRP3 (+/+) or NLRP3 (-/-) macrophages and PDAC cells. Cell growth was analyzed by a Cell Counting Kit-8 (CCK-8) assay. Cell invasiveness and migratory potential were analyzed by transwell cell invasion assay and cell migration assay, respectively. PDAC formation and lung metastasis were analyzed in a mouse model of PDAC with and without NLRP3 knockout.ResultsGEO database analysis revealed significant alteration in genes that regulate macrophage polarization in NLRP3-depleted macrophages. NLRP3-depletion in macrophages seemed to favor an M1/M2b polarization. In vitro, the presence of NLRP3 in macrophages led to M2a/c/d TAM-like polarization when they were cocultured with PDAC cells. Conversely, NLRP3 depletion in macrophages led to M1/M2b polarization when they were cocultured with PDAC cells. NLRP3-depletion significantly inhibited tumor growth and stage progression in a mouse model of PDAC and significantly reduced the occurrence of lung metastasis.ConclusionsOur results suggested that NLRP3 activation in TAM enhanced lung metastasis of PDAC through regulation of TAM polarization.

Dataset Information

Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma.

Publications

Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma.

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