Tumor Stroma Interactions Induce Chemoresistance in Pancreatic Ductal Carcinoma Cells Involving Increased Secretion and Paracrine Effects of Nitric Oxide and Interleukin-1β

Müerköster, Susanne Sebens; Wegehenkel, Kai; Arlt, Alexander; Witt, Maike; Sipos, Bence; Kruse, Marie Luise; Sebens, Thorsten; Klöppel, Günter; Kalthoff, Holger; Fölsch, Ulrich R.; Schäfer, Heiner

doi:10.1158/0008-5472.can-03-1860

Cited by 244 publications

(219 citation statements)

References 31 publications

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“…Multiple lines of evidence support the link between NO and chemoresistance (47)(48)(49)(50). Herein, we show that O-ASCs regulate cancer cells' response to chemo-drugs through the NO pathway.…”

Section: Discussionmentioning

confidence: 58%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that promote endometrial and ovarian tumor proliferation, migration, and drug resistance. The mechanistic underpinnings of O-ASCs' role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of L-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using L-arginase and NOS inhibition in cancer cells using N G -nitro-L-arginine methyl ester (L-NAME), we demonstrate that patientderived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells use O-ASCsecreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells, leading to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASCmediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through L-arginase, along with targeting microenvironment-secreted factors using L-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers. Cancer Res; 75(2); 456-71. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 58%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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“…considering that plasma galectin-1 levels were elevated from early stages of crc, it is possible that galectin-1 has some relevance to tumor maintenance. recent evidence suggests that the interaction between tumor cells and surrounding stroma plays a critical role in tumor growth, invasion, metastasis, angiogenesis, and chemoresistance (29)(30)(31)(32)(33)(34). It has been shown that galectin-1 regulates cell migration and that galectin-1 binding sites are displayed on cell surfaces in most colon cancer cell lines, while only one of them actually expresses galectin-1 (16).…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of circulating galectins as colorectal cancer markers

et al. 2011

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Abstract. the utility of ceA and cA19-9 as colorectal carcinoma (crc) markers is limited and development of additional reliable markers is under investigation. We previously showed that galectin-1 is overexpressed in crc tissues. If such a protein leaks into the peripheral circulation, it might constitute a tumor marker candidate. Here, we test the hypothesis that the levels of circulating galectins could reflect the presence of crc and/or its progression state. We constructed sandwich elIsAs for galectin-1/-2/-3/-4/-7 and determined their plasma concentrations in 105 crc patients and 100 healthy volunteers (control). Matched pair samples of 56 patients pre-and post-surgery were also subjected to elIsA analysis. circulating levels of galectin-1/-3/-4 in crc patients were significantly higher compared to those in controls. Galectin-1 and galectin-4 levels significantly decreased after surgery (p<0.01), and the level of galectin-4 in most patients fell below the cut-off value. the levels of circulating galectin-4 significantly increased as the tumor stage progressed (P<0.001), whereas those for galectin-1 were relatively high from an early stage. combined use of galectin-4 with ceA and/or cA19-9 markedly increased the proportion of crc patients who were positive for tumor markers (from 33.3 to 59.0% for ceA and from 17.1 to 51.4% for cA19-9). our data show that galectin-4 may be a tumor marker for use in patient follow-up, while galectin-1 could be used for tumor screening. In particular, galectin-4 can be useful as a complementary marker when combined with ceA/cA19-9 to improve crc follow-up.

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“…Using IKKb ablation in myeloid cells in a carcinogen/inflammation model for colorectal cancer, Greten et al (2004) showed that NF-kB controls the ability of invading myeloid cells to produce cytokines, which are involved in promoting tumor growth. In another interesting study, NF-kB appears to mediate an IL-1/nitric oxide paracrine growth loop involving stromal fibroblasts and pancreatic neoplastic cells (Muerkoster et al, 2004).…”

Section: Nf-jb In the Tumor Micro-environmentmentioning

confidence: 94%

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

2006

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Tumor Stroma Interactions Induce Chemoresistance in Pancreatic Ductal Carcinoma Cells Involving Increased Secretion and Paracrine Effects of Nitric Oxide and Interleukin-1β

Abstract: ABSTRACT

Cited by 244 publications

References 31 publications

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

Clinical significance of circulating galectins as colorectal cancer markers

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

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