Understanding the tumour micro‐environment communication network from an NOS2/COX2 perspective

Basudhar, Debashree; Bharadwaj, Gaurav; Somasundaram, Veena; Cheng, Robert; Ridnour, Lisa A.; Fujita, Mayumi; Lockett, Stephen; Anderson, Stephen; McVicar, Daniel W.; Wink, David A.

doi:10.1111/bph.14488

Cited by 38 publications

(29 citation statements)

References 252 publications

(283 reference statements)

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“…Low flux of NO produced via NOS3 has been demonstrated to activate MEK-ERK and JAK-STAT pathways [44], and activation of these pathways is known to induce pro-metastatic and CSC-related genes [[45], [46], [47], [48], [49], [50]]. NOS2 is also known to activate MEK-ERK and PI3K-AKT pathways [51], which can induce CSC related genes [[45], [46], [47],51,52]. Thus, MEK-ERK, JAK-STAT and PI3-AKT pathways may be important in INV.…”

Section: Resultsmentioning

confidence: 99%

Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype

et al. 2019

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Pancreatic cancer is a highly metastatic tumor with an extremely low 5-year survival rate. Lack of efficient diagnostics and dearth of effective therapeutics that can target the cancer as well as the microenvironment niche are the reasons for limited success in treatment and management of this disease. Cell invasion through extracellular matrix (ECM) involves the complex regulation of adhesion to and detachment from ECM and its understanding is critical to metastatic potential of pancreatic cancer. To understand the characteristics of these cancer cells and their ability to metastasize, we compared human pancreatic cancer cell line, PANC-1 and its invading phenotype (INV) collected from transwell inserts. The invasive cell type, INV, exhibited higher resistance to Carbon-ion radiation compared to whole cultured (normally dish-cultured) PANC-1 (WCC), and had more efficient in vitro spheroid formation capability. Invasiveness of INV was hampered by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide (NO) plays a cardinal role in PANC-1 invasion. In addition, in vitro studies indicated that a MEK-ERK-dependent, JAK independent mechanism through which NOS/NO modulate PANC-1 invasiveness. Suspended INV showed enhanced NO production as well as induction of several pro-metastatic, and stemness-related genes. NOS inhibitor, l -NAME, reduced the expression of these pro-metastatic or stemness-related genes, and dampened spheroid formation ability, suggesting that NO can potentially influence pancreatic cancer aggressiveness. Furthermore, xenograft studies with INV and WCC in NSG mouse model revealed a greater ability of INV compared to WCC, to metastasize to the liver and l -NAME diminished the metastatic lesions in mice injected with INV. Overall, data suggest that NO is a key player associated with resistance to radiation and metastasis of pancreatic cancer; and inhibition of NOS demonstrates therapeutic potential as observed in the animal model by specifically targeting the metastatic cells that harbor stem-like features and are potentially responsible for relapse.

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Section: Resultsmentioning

confidence: 99%

Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype

et al. 2019

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“…Previous data suggested that co-expression of NOS2 and COX2 is a strong prognostic indicator in TNBC patients [66], also contributing to tumor aggressiveness and poor patient prognosis [67].…”

Section: Discussionmentioning

confidence: 99%

Novel Medicinal Mushroom Blend as a Promising Supplement in Integrative Oncology: A Multi-Tiered Study using 4T1 Triple-Negative Mouse Breast Cancer Model

Roda

Luca

Iorio

et al. 2020

IJMS

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Although medicinal mushroom extracts have been proposed as promising anti-cancer agents, their precise impacts on metastatic breast cancer are still to be clarified. For this purpose, the present study exploited the effect of a novel medicinal mushroom blend, namely Micotherapy U-care, in a 4T1 triple-negative mouse breast cancer model. Mice were orally administered with Micotherapy U-care, consisting of a mixture of Agaricus blazei, Ophiocordyceps sinensis, Ganoderma lucidum, Grifola frondosa, and Lentinula edodes. The syngeneic tumor-bearing mice were generated by injecting 4T1 cells in both supplemented and non-supplemented mice. After sacrifice 35 days later, specific endpoints and pathological outcomes of the murine pulmonary tissue were evaluated. (i) Histopathological and ultrastructural analysis and (ii) immunohistochemical assessment of TGF-ß1, IL-6 and NOS2, COX2, SOD1 as markers of inflammation and oxidative stress were performed. The QoL was comparatively evaluated. Micotherapy U-care supplementation, starting before 4T1 injection and lasting until the end of the experiment, dramatically reduced the pulmonary metastases density, also triggering a decrease of fibrotic response, and reducing IL-6, NOS, and COX2 expression. SOD1 and TGF-ß1 results were also discussed. These findings support the valuable potential of Micotherapy U-care as adjuvant therapy in the critical management of triple-negative breast cancer.

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“…The notion of communication through intercellular signaling has classically involved structure-function interactions. In addition, redox regulated signaling has provided new strategies to enhance cancer therapy that have included modification of signal transduction, immune signaling, inhibition of nitric oxide synthase 2 (NOS2), and cyclooxygenase 2 (COX2), which have all shown promise in preclinical and even clinical trials [4][5][6]. Furthermore, NOS2/COX2 are linked to poor outcome and collaborate in feedforward loops in both cancer and immune cells in several tumor types, with ER-breast cancer being the best example [7][8][9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment

McGinity

Palmieri

Somasundaram

et al. 2021

IJMS

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The metabolic requirements and functions of cancer and normal tissues are vastly different. Due to the rapid growth of cancer cells in the tumor microenvironment, distorted vasculature is commonly observed, which creates harsh environments that require rigorous and constantly evolving cellular adaption. A common hallmark of aggressive and therapeutically resistant tumors is hypoxia and hypoxia-induced stress markers. However, recent studies have identified alterations in a wide spectrum of metabolic pathways that dictate tumor behavior and response to therapy. Accordingly, it is becoming clear that metabolic processes are not uniform throughout the tumor microenvironment. Metabolic processes differ and are cell type specific where various factors promote metabolic heterogeneity within the tumor microenvironment. Furthermore, within the tumor, these metabolically distinct cell types can organize to form cellular neighborhoods that serve to establish a pro-tumor milieu in which distant and spatially distinct cellular neighborhoods can communicate via signaling metabolites from stroma, immune and tumor cells. In this review, we will discuss how biochemical interactions of various metabolic pathways influence cancer and immune microenvironments, as well as associated mechanisms that lead to good or poor clinical outcomes.

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Understanding the tumour micro‐environment communication network from an NOS2/COX2 perspective

Cited by 38 publications

References 252 publications

Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype

Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype

Novel Medicinal Mushroom Blend as a Promising Supplement in Integrative Oncology: A Multi-Tiered Study using 4T1 Triple-Negative Mouse Breast Cancer Model

Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment

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