Inflammatory cytokines induce vascular endothelial growth factor‑C expression in melanoma‑associated macrophages and stimulate melanoma lymph node metastasis

Peppicelli,Silvia; Bianchini,Francesca; Calorini,Lido

doi:10.3892/ol.2014.2297

Inflammatory cytokines induce vascular endothelial growth factor‑C expression in melanoma‑associated macrophages and stimulate melanoma lymph node metastasis

Authors:
- Silvia Peppicelli
- Francesca Bianchini
- Lido Calorini
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Affiliations: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
Published online on: June 30, 2014 https://doi.org/10.3892/ol.2014.2297
Pages: 1133-1138

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Abstract

Lymph node colonization by tumor cells is one of the key determinants of melanoma staging and prognosis, and tumor‑associated macrophages (TAMs) are the predominant type of inflammatory cell in the tumor environment which secretes vascular endothelial growth factor (VEGF)‑C, the most potent lymphangiogenic growth factor. In the present study, to elucidate the mechanism involved in VEGF‑C expression in TAMs, murine peritoneal macrophages were co‑cultivated with syngeneic B16 melanoma cells to mimic the reciprocal interactions between tumor cells and macrophages found in spontaneous tumors. In the present study, upon contact with tumor cells, macrophages were found to express a higher level of VEGF‑C which was associated with an increase in the expression of IL‑1β and TNF‑α and their receptors. Antibodies against the IL‑1β and TNF‑α receptors were added to media that had been conditioned by the macrophage‑tumor cell co‑cultures and inhibition of VEGF-C was observed in macrophages co‑cultivated with the tumor cells. Furthermore, when IL‑1β and TNF‑α were used at a non‑toxic level, they enhanced peritoneal lymph node colonization by melanoma cells. Thus, in the present study, macrophagic IL‑1β and TNF‑α were observed to promote VEGF‑C expression in TAMs, as well as melanoma lymph node metastasis, suggesting that inhibiting the signaling between tumor cells and TAMs may be required to inhibit lymphangiogenesis and lymph node metastasis.

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1	Dadras SS, Paul T, Bertoncini J, et al: Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol. 162:1951–1960. 2003.
2	Tammela T and Alitalo K: Lymphangiogenesis: Molecular mechanisms and future promise. Cell. 140:460–76. 2010.
3	Alitalo K, Tammela T and Petrova TV: Lymphangiogenesis in development and human disease. Nature. 438:946–953. 2005.
4	Achen MG, McColl BK and Stacker SA: Focus on lymphangiogenesis in tumor metastasis. Cancer Cell. 7:121–127. 2005.
5	Karkkainen MJ, Haiko P, Sainio K, et al: Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 5:74–80. 2004.
6	Su JL, Yen CJ, Chen PS, et al: The role of the VEGF-C/VEGFR-3 axis in cancer progression. Br J Cancer. 96:541–545. 2007.
7	Ji RC: Lymphatic endothelial cells, tumor lymphangiogenesis and metastasis: New insights into intratumoral and peritumoral lymphatics. Cancer Metastasis Rev. 25:677–694. 2006.
8	Su JL, Yang PC, Shih JY, et al: The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell. 9:209–223. 2006.
9	Schoppmann SF, Birner P, Stöckl J, et al: Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol. 161:947–956. 2002.
10	Skobe M, Hamberg LM, Hawighorst T, et al: Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol. 159:893–903. 2001.
11	Kerjaschki D: The crucial role of macrophages in lymphangiogenesis. J Clin Invest. 115:2316–2319. 2005.
12	Chen TR: In situ detection of mycoplasma contamination in cell cultures by fluorescent Hoechst 33258 stain. Exp Cell Res. 104:255–262. 1977.
13	Calorini L, Bianchini F, Mannini A, Mugnai G and Ruggieri S: Enhancement of nitric oxide release in mouse inflammatory macrophages co-cultivated with tumor cells of a different origin. Clin Exp Metastasis. 22:413–419. 2005.
14	Bianchini F, Massi D, Marconi C, et al: Expression of cyclo-oxygenase-2 in macrophages associated with cutaneous melanoma at different stages of progression. Prostaglandins Other Lipid Mediat. 83:320–328. 2007.
15	Marconi C, Bianchini F, Mannini A, et al: Tumoral and macrophage uPAR and MMP-9 contribute to the invasiveness of B16 murine melanoma cells. Clin Exp Metastasis. 25:225–231. 2008.
16	Varney ML, Johansson SL and Singh RK: Tumour-associated macrophage infiltration, neovascularization and aggressiveness in malignant melanoma: role of monocyte chemotactic protein-1 and vascular endothelial growth factor-A. Melanoma Res. 15:417–425. 2005.
17	Condeelis J and Pollard JW: Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 124:263–266. 2006.
18	Qian BZ and Pollard JW: Macrophage diversity enhances tumor progression and metastasis. Cell. 141:39–51. 2010.
19	Barbera-Guillem E, Nyhus JK, Wolford CC, Friece CR and Sampsel JW: Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. Cancer Res. 62:7042–7049. 2002.
20	Ristimäki A, Narko K, Enholm B, Joukov V and Alitalo K: Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J Biol Chem. 273:8413–8418. 1998.
21	Peppicelli S, Bianchini F, Contena C, Tombaccini D and Calorini L: Acidic pH via NF-κB favours VEGF-C expression in human melanoma cells. Clin Exp Metastasis. 30:957–967. 2013.
22	Jancic CC, Cabrini M, Gabelloni ML, Rodríguez Rodrigues C, Salamone G, Trevani AS and Geffner J: Low extracellular pH stimulates the production of IL-1β by human monocytes. Cytokine. 57:258–268. 2012.
23	Stetler-Stevenson WG and Yu AE: Proteases in invasion: matrix metalloproteinases. Semin Cancer Biol. 11:143–152. 2001.
24	Vidal-Vanaclocha F, Alvarez A, Asumendi A, Urcelay B, Tonino P and Dinarello CA: Interleukin 1 (IL-1)-dependent melanoma hepatic metastasis in vivo; increate endothelial adherence by IL-1-induced mannose receptors and growth factor production in vitro. J Natl Cancer Inst. 88:198–205. 1996.
25	Balkwill F: Tumour necrosis factor and cancer. Nat Rev Cancer. 9:361–371. 2009.
26	Lachman LB, Dinarello CA, Llansa ND and Fidler IJ: Natural and recombinant human interleukin 1-beta is cytotoxic for human melanoma cells. J Immunol. 136:3098–3102. 1986.