Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: Possible involvement of TNFα and IL-1α

Torisu, Hitoe; Ono, Masahiro; Kiryu, Hiromaro; Furue, Masutaka; Ohmoto, Yasukazu; Nakayama, Juichiro; Nishioka, Yuko; Sone, Saburo; Kuwano, Michihiko

doi:10.1002/(sici)1097-0215(20000115)85:2%3c182::aid-ijc6%3e3.0.co;2-m

Cited by 314 publications

(169 citation statements)

References 8 publications

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“…Similar paracrine interactions between melanomas and macrophages have also been observed. 35 Taken together, these findings underscore the complex interactions between HNSCC and one particular type of stromal cell present in the tumor microenvironment. It is likely that similar paracrine interactions involving tumor cells and other stromal cells, such as endothelial cells, fibroblasts and lymphocytes, also occur.…”

Section: Activated Macrophages Induce Hnscc Tumor Cells To Secrete Himentioning

confidence: 72%

Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages

et al. 2001

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Angiogenesis, an essential step in the development of neoplasia, is a complex process that involves the interaction of tumor cells with stromal cells. Tumor-associated macrophages (TAMs) can participate in the induction of tumor angiogenesis and are thought to be of prognostic value in some neoplasms. We have investigated how macrophages contribute to angiogenesis in head-and-neck squamous-cell carcinoma (HNSCC) and have found that tumor cells attract monocytes and activate them to secrete angiogenic factors. The attraction of macrophages was due to the secretion of monocyte chemotactic protein-1 and TGF-␤1 by tumor cells, while tumor production of TGF-␤1 was responsible for activating macrophages. In addition, activated macrophages produced cytokines that acted in a paracrine fashion by secreting both TNF-␣ and IL-1, which in turn stimulated tumor cells to secrete increased levels of IL-8 and VEGF. These data demonstrate that TAMs play an important role in the in vivo induction of angiogenesis in HNSCC and suggest that antiangiogenic therapies for HNSCC and perhaps other neoplasms must include strategies that will block the ability of tumor cells to recruit macrophages into the tumor microenvironment.Key words : squamous-cell carcinoma; angiogenesis; macrophages; angiogenic loop; head-and-neck cancer Angiogenesis, the growth of new blood vessels from pre-existing ones, is an essential phenotype for tumor formation. 1 Expression of the angiogenic phenotype in the tumor micro-environment is a complex process involving the interaction of many different cell types. The interplay between tumor cells and the various constituents of the surrounding stroma is thought to be critically important in various aspects of tumor biology, including angiogenesis. 2 Macrophages, part of the tumor stroma, are members of the mononuclear phagocyte system of inflammatory cells. A very heterogeneous group, they perform a wide variety of functions depending on the physiologic or pathophysiologic condition to which they are recruited. Given the remarkable versatility of macrophages, it is not surprising that they participate in the induction of tumor angiogenesis. 3 There is a great deal of interest in developing chemotherapeutic clinical trials that are based on anti-angiogenic therapies. 4 However, one of the major challenges for designing such therapies is that there are numerous direct and indirect mechanisms by which tumors can induce new blood vessel growth, including eliciting the help of various stromal cells. Therefore, it is reasonable to assume that successful anti-angiogenic protocols must address each of the possible mechanisms by which tumors can induce new blood vessel growth. Our aim was to identify additional potential mechanisms by which human head-and-neck squamous-cell carcinoma (HNSCC) may induce neovascularization in vivo. Specifically, we investigated how macrophages contribute to angiogenesis in HNSCC and show that HNSCC tumor cells attract monocytes and activate them to secrete angiogenic factors. In additio...

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Section: Activated Macrophages Induce Hnscc Tumor Cells To Secrete Himentioning

confidence: 72%

Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages

et al. 2001

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“…These include monocyte chemotactic protein-1, M-CSF, GM-CSF and VEGF-C (Skobe et al, 2001). Tumour-associated macrophages form a major component of the inflammatory cell infiltrate within and around primary and metastatic melanomas, and TAM numbers have been shown to correlate with melanoma invasion (Torisu et al, 2000). These TAMs produce cytokines and growth factors, including IL-8, VEGF and FGF, which stimulate tumour growth and angiogenesis in melanomas (Torisu et al, 2000;Nesbit et al, 2001;Shimizu et al, 2001;Callejo et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Tumour-associated macrophages form a major component of the inflammatory cell infiltrate within and around primary and metastatic melanomas, and TAM numbers have been shown to correlate with melanoma invasion (Torisu et al, 2000). These TAMs produce cytokines and growth factors, including IL-8, VEGF and FGF, which stimulate tumour growth and angiogenesis in melanomas (Torisu et al, 2000;Nesbit et al, 2001;Shimizu et al, 2001;Callejo et al, 2004). We have previously shown that mouse and human TAMs isolated from primary and metastatic breast carcinomas are capable of differentiation into TRAP þ osteoclastic cells capable of extensive lacunar resorption when these cells are co-cultured with bone-derived stromal cells and M-CSF (Quinn et al, 1992(Quinn et al, , 1994.…”

Section: Discussionmentioning

confidence: 99%

Malignant melanoma and bone resorption

et al. 2006

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The cellular and humoral mechanisms accounting for osteolysis in skeletal metastases of malignant melanoma are uncertain. Osteoclasts, the specialised multinucleated cells that carry out bone resorption, are derived from monocyte/macrophage precursors. We isolated tumour-associated macrophages (TAMs) from metastatic (lymph node/skin) melanomas and cultured them in the presence and absence of osteoclastogenic cytokines and growth factors. The effect of tumour-derived fibroblasts and melanoma cells on osteoclast formation and resorption was also analysed. Melanoma TAMs (CD14 þ /CD51À) differentiated into osteoclasts (CD14À/CD51 þ ) in the presence of receptor activator for nuclear factor kB ligand (RANKL) and macrophage-colony stimulating factor. Tumour-associated macrophage-osteoclast differentiation also occurred via a RANKL-independent pathway when TAMs were cultured with tumour necrosis factor-a and interleukin (IL)-1a. RT -PCR showed that fibroblasts isolated from metastatic melanomas expressed RANKL messenger RNA and the conditioned medium of cultured melanoma fibroblasts was found to be capable of inducing osteoclast formation in the absence of RANKL; this effect was inhibited by the addition of osteoprotegerin (OPG). We also found that cultured human SK-Mel-29 melanoma cells produce a soluble factor that induces osteoclast differentiation; this effect was not inhibited by OPG. Our findings indicate that TAMs in metastatic melanomas can differentiate into osteoclasts and that melanoma fibroblasts and melanoma tumour cells can induce osteoclast formation by RANKL-dependent and RANKL-independent mechanisms, respectively.

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“…TP-mediated macrophage chemotaxia may, therefore, contribute to the angiogenic process, as activated macrophages, apart from producing TP, usually secrete a variety of pro-angiogenic and angiogenic cytokines (Sunderkotter et al, 1994;Ono et al, 1999;White et al, 2001). The angiogenic relevance of an intense macrophage infiltration of the tumour stroma has been shown in a variety of other human tumours including breast (Leek et al, 2000), endometrial (Hashimoto et al, 2000) and lung carcinomas (Takanami et al, 1999), gliomas and malignant melanomas (Torisu et al, 2000).…”

Section: Molecular and Cellular Pathologymentioning

confidence: 93%

Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis

et al. 2002

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Thymidine phosphorylase is an angiogenic factor primarily expressed by cancer cells, stromal cells and tumour-associated macrophages in many human malignancies. These different types of thymidine phosphorylase-expressing cells, however, may have a distinct place in the angiogenic process, and this question was addressed in the present study. A series of 20 normal/ hyperplastic prostate glands and 60 prostate carcinomas was investigated by immunohistochemistry, using specific antibodies for thymidine phosphorylase (P-GF.44C), tumour-associated macrophages (CD68), endothelium (CD31) and prostate specific antigen (ER-PR8). Thymidine phosphorylase expression by normal and hyperplastic epithelial or stromal cells occurred almost exclusively in the context of an intense lymphocytic infiltrate. High thymidine phosphorylase cancer cells and thymidine phosphorylase stromal cells expression was associated with high angiogenesis in prostate carcinomas, and this significant association was extended to include both tumour-associated macrophages and tumour-infiltrating lymphocytes. Thymidine phosphorylase expression and tumour-infiltrating lymphocytes were related inversely with prostate specific antigen reactivity. In conclusion, thymidine phosphorylase is a major angiogenic factor in prostate carcinomas and its up-regulation is likely to occur in the context of a host immune response.

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Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: Possible involvement of TNFα and IL-1α

Cited by 314 publications

References 8 publications

Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages

Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages

Malignant melanoma and bone resorption

Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis

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