Arginine metabolism in tumor-associated macrophages in cutaneous malignant melanoma: evidence from human and experimental tumors

Massi, Daniela; Marconi, Chiara; Franchi, Alessandro; Bianchini, Francesca; Paglierani, Milena; Ketabchi, Sheyda; Miracco, Clelia; Santucci, Marco; Calorini, Lido

doi:10.1016/j.humpath.2007.02.018

Cited by 52 publications

(44 citation statements)

References 32 publications

(35 reference statements)

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“…We recently provided evidence that TAMs of early melanomas show an activated phenotype in which iNOS prevails on arginase. However, in an in vitro model the release of high NO levels by TAMs required that tumor microenvironment contains activated lymphocytes or natural killer cells producing IFN-g. 27 Thus, it may be possible that also iNOS expressed by nonmelanoma cells contribute to lymphangiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

et al. 2009

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Cutaneous melanoma preferentially metastasizes via the lymphatic route. However, the mechanisms of lymphatic invasion and metastasis to regional lymph nodes are poorly understood. Nitric oxide is a free radical molecule synthesized from L-arginine by nitric oxide synthases that plays a critical role in various physiological and pathological processes, including tumor growth and angiogenesis. We have tested whether inducible nitric oxide synthase expression correlates with lymphatic vessel density identified with D2-40 antibody and/or blood microvessel density identified with CD105/endoglin in a series of melanocytic nevi (n ¼ 28) and cutaneous melanomas (n ¼ 38), representative of various pT. Inducible nitric oxide synthase expression was significantly lower in melanocytic nevi in comparison with primary and metastatic melanomas (Po0.001). Mean microvessel density was significantly higher in primary and metastatic melanomas in comparison with melanocytic nevi (Po0.001 for intratumoral and P ¼ 0.001 for peritumoral vessels). Vertical growth phase melanomas showed a higher intratumoral microvessel density in comparison with radial growth phase melanomas (P ¼ 0.02). The number of peritumoral lymphatics was significantly lower in nevi as compared with primary and metastatic melanomas (P ¼ 0.01). No correlation between microvessel or lymphatic vessel and clinical outcome was found in melanomas. A significant direct correlation was observed between inducible nitric oxide synthase immunostaining in melanocytic tumor cells and the density of lymphatic vessels (peritumoral: P ¼ 0.001; intratumoral: P ¼ 0.08), and the density of peritumoral blood microvessel (P ¼ 0.02). Our findings support the hypothesis that inducible nitric oxide synthase is implicated not only in blood, but also in lymphatic vascular neoformation in melanoma. Mechanistic studies are needed to address the possibility that inducible nitric oxide synthase controls lymphangiogenesis, dissemination and lymphatic borne metastases. Keywords: iNOS; CD105; D2-40; microvessel density; melanoma; nevi Cutaneous melanoma metastasizes at least initially through the lymphatic route and lymph node metastasis is currently still a major determinant for patients staging and clinical management. The mechanisms of lymphatic invasion and metastasis to regional lymph nodes are mostly unknown and whether human tumors promote de novo lymphangiogenesis is still unclear. Although the pathways that regulate tumorrelated angiogenesis have been partially investigated, poor information is available on the processes that result in lymphangiogenesis in melanoma.Nitric oxide (NO) is a diatomic free radical molecule synthesized from L-arginine by NO synthases (NOS) that plays a critical role in various physiological and pathological processes, including tumor growth. Although the Ca 2 þ -dependent isoforms NOS1 and NOS3 are constitutively expressed by neural and endothelial cells, the Ca 2 þ -independent form (NOS2 or iNOS) can be induced by many cell types upon stimulation by inflamma...

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Section: Discussionmentioning

confidence: 99%

Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

et al. 2009

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“…1B) (9,36). Melanoma-associated macrophages have been revealed to have a distorted balance between the production of inducible nitric oxide synthase (iNOS) and arginase (36). Macrophages use arginine to produce NO by iNOS, or to produce ornithine through arginase activity (36).…”

Section: Macrophages In Skin Melanomasmentioning

confidence: 99%

“…Macrophages use arginine to produce NO by iNOS, or to produce ornithine through arginase activity (36). NO is primarily cytotoxic and ornithine production promotes the proliferation of tumor cells (36). It has been demonstrated that in clinically less advanced melanomas, iNOS is more active compared with arginase, and this is stimulated by contact with melanoma cells (36).…”

Section: Macrophages In Skin Melanomasmentioning

confidence: 99%

“…NO is primarily cytotoxic and ornithine production promotes the proliferation of tumor cells (36). It has been demonstrated that in clinically less advanced melanomas, iNOS is more active compared with arginase, and this is stimulated by contact with melanoma cells (36). In the case of more advanced primary lesions, a significant reduction in the number of macrophages with a higher percentage of iNOS has been observed (36).…”

Section: Macrophages In Skin Melanomasmentioning

confidence: 99%

“…It has been demonstrated that in clinically less advanced melanomas, iNOS is more active compared with arginase, and this is stimulated by contact with melanoma cells (36). In the case of more advanced primary lesions, a significant reduction in the number of macrophages with a higher percentage of iNOS has been observed (36). It is notable that NO released by macrophages possesses anticancer properties only in the presence of INFγ produced by natural killer cells (36).…”

Section: Macrophages In Skin Melanomasmentioning

confidence: 99%

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Macrophages in skin melanoma-the key element in melanomagenesis (Review)

Pieniążek¹,

Matkowski

Donizy

2018

Oncol Lett

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Abstract. Cutaneous melanoma is an aggressive cancer and its onset and growth are associated, through direct and indirect interactions, with the cancer microenvironment. The microenvironment comprises a dynamic complex of numerous types of cells (due to histogenesis) that constantly interact with each other through multiple cytokines and signaling proteins. Macrophages are one of the most thoroughly studied pleiotropic cells of the immune system. One of their major cytophysiological functions is their involvement in phagocytosis. Previous studies examining the microenvironment of melanomas and tumor-associated macrophages have revealed that they are involved in all stages of melanomagenesis. In the case of cancer initiation, they form an inflammatory microenvironment and then suppress the anticancer activity of the immune system, stimulate angiogenesis, enhance migration and invasion of the cancer cells, and ultimately contribute to the metastatic process. The present review provides a detailed overview on the function of macrophages in the melanoma microenvironment. IntroductionMelanomas are a rare but aggressive cutaneous type of cancer in humans (1). At the dissemination stage in a majority of cases, the disease is resistant to treatment with cytostatics and radiotherapy (1). Therefore, the identification of novel molecular mechanisms involved in the melanomagenesis process and tumor progression have enabled the production of targeted therapies that yield notable effects (1). The basis for melanomagenesis is the accumulation of genetic disorders in the melanocyte (the most frequent ones include the following mutations: B-Raf proto-oncogene, serine/threonine kinase, N-Ras proto-oncogene, GTPase and phosphatase and tensin homolog) (1). However, only the interaction between microenvironment elements and genetic changes in the melanocyte result in the ultimate transformation of a dysplastic melanocyte into a melanoma cell, and at further stages result in the local invasion and dissemination of the primary lesion (1). It is the microenvironment that is one of the key elements of cancer formation and is being studied at present.A melanoma microenvironment is a markedly heterogenic population of cells that involves fibroblasts, macrophages, lymphocytes, other immune system cells, adipocytes and cells that form the structural elements of cutaneous blood vessels sunk in the extracellular matrix (2). The aforementioned complex network of cellular associations are constantly interacting through direct contact and active protein substances including secretory proteins (e.g., metalloproteinases or

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Immunosuppressive enzymes in the tumor microenvironment

Molinier‐Frenkel

Castellano

2017

FEBS Letters

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Antigen encounter by T lymphocytes induces important metabolic changes. Antitumor T lymphocytes enter in a metabolic competition with tumors, which divert feedback mechanisms of the immune response. Immunosuppressive enzymes, modifying the nutrient availability and leading to the production of toxic catabolites, represent one of these mechanisms, contributing to the metabolic halo in which T lymphocytes evolve during immune responses. Two classes of immunosuppressive enzymes, expressed by the tumor cells or by cells of the microenvironment, have been described: those catabolizing essential or semiessential amino acids, tryptophan, arginine, and phenylalanine and the ectoenzymes, which degrade the ATP to produce adenosine. These enzymes are described, as well as some of the ongoing clinical trials aiming to block them in cancer treatment.

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Arginine metabolism in tumor-associated macrophages in cutaneous malignant melanoma: evidence from human and experimental tumors

Cited by 52 publications

References 32 publications

Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

Macrophages in skin melanoma-the key element in melanomagenesis (Review)

Immunosuppressive enzymes in the tumor microenvironment

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