Serum from morbidly obese patients affects melanoma cell behavior in vitro

Authors

  • Débora Mocellin Postgraduate Program in Pharmacy, Health Science Center, Federal University of Santa Catarina, Florianópolis, SC, Brazil
  • Letícia de Oliveira Souza Bratti Postgraduate Program in Pharmacy, Health Science Center, Federal University of Santa Catarina, Florianópolis, SC, Brazil
  • Adny Henrique Silva Postgraduate Program in Biochemistry, Biological Sciences Center, Federal University of Santa Catarina, Florianópolis, SC, Brazil https://orcid.org/0000-0002-8511-3973
  • Laura Sartori Assunção Postgraduate Program in Pharmacy, Health Science Center, Federal University of Santa Catarina, Florianópolis, SC, Brazil
  • Iara Fabricia Kretzer Department of Clinical Analysis, Health Science Center, Federal University of Santa Catarina, Florianópolis, SC, Brazil
  • Fabíola Branco Filippin Monteiro Postgraduate Program in Pharmacy, Health Science Center, Federal University of Santa Catarina, Florianópolis, SC, Brazil; Department of Clinical Analysis, Health Science Center, Federal University of Santa Catarina, Florianópolis, SC, Brazil https://orcid.org/0000-0003-4313-1783

DOI:

https://doi.org/10.1590/s2175-979020201000X42e19375%20%20

Keywords:

Melanoma, Tumor progression, Inflammation, Morbidly obesity

Abstract

Here we examined whether serum from obese patients could create a growth-enhancing microenvironment that alters gene expression in BRAF- and NRAS-mutated melanoma cell lines. SK-Mel-28 (BRAF-mutated) and Sk-Mel-147 (NRAS-mutated) cells were treated with pooled serum from 10 severely obese patients (BMI > 40 kg/m2), pooled serum from 6 healthy lean individuals (BMI = 18.5-24.9 kg/m2), or recombinant TNF-α. We found that obese patient serum enhanced migration capacity and increased NRAS expression levels in both BRAF- and NRAS-mutated melanoma cells. Although TNF-α is the major obesity-related cytokine and TNF-α levels were found to be increased in the serum of obese individuals, this cytokine made only a modest contribution to the migration capacity of melanoma cells. These results indicate that other components present in the serum of severely obese patients may be responsible for enhancing the migration capacity of melanoma cells. As TNF-α alone did not seem to significantly affect tumor cell behavior, anti-tumor strategies aimed at blocking TNF-α should be considered with caution in future studies, particularly when in vitro models are used as screening platforms for antitumor activity.

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References

Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab. 2000;11(8):327-32.

Apovian CM, Bigornia S, Mott M, Meyers MR, Ulloor J, Gagua M, et al. Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arterioscler Thromb Vasc Biol. 2008;28(9):1654-9.

Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539-45.

Balkwill F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 2006;25(3):409-16.

Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet . 2014;384(9945):755-65.

Cai H, Song C, Endoh I, Goyette J, Jessup W, Freedman SB, et al. Serum amyloid A induces monocyte tissue factor. J Immunol. 2007;178(3):1852-60.

Cantón I, Eves PC, Szabo M, Vidal-Vanacloch F, Sisley K, Rennie IG, et al. Tumor necrosis factor alpha increases and alpha-melanocyte-stimulating hormone reduces uveal melanoma invasion through fibronectin. J Invest Dermatol. 2003;121(3):557-563.

Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625-38.

Castellano E, Downward J. RAS Interaction with PI3K: More Than Just Another Effector Pathway. Genes Cancer. 2011;2(3):261-74.

Castellano E, Molina-Arcas M, Krygowska AA, East P, Warne P, Nicol A, et al. RAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression. Nat Commun. 2016;7:11245.

Chan DC, Chen CJ, Chu HC, Chang WK, Yu JC, Chen YJ, et al. Evaluation of serum amyloid A as a biomarker for gastric cancer. Ann Surg Oncol. 2007;14(1):84-93.

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-54.

Daveri E, Valacchi G, Romagnoli R, Maellaro E, Maioli E. Antiproliferative effect of rottlerin on Sk-Mel-28 melanoma cells. Evid Based Complement Alternat Med. 2015;2015:1-9.

De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes. 2013;2013:1-11.

Fan Y, Mao R, Yang J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell. 2013;4(3):176-85.

Filippin-Monteiro FB, de Oliveira EM, Sandri S, Knebel FH, Albuquerque RC, Campa A. Serum amyloid A is a growth factor for 3T3-L1 adipocytes, inhibits differentiation and promotes insulin resistance. Int J Obes (Lond). 2011;36(8):1032-9.

Furlaneto CJ, Campa A. A novel function of serum amyloid A: a potent stimulus for the release of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-8 by human blood neutrophil. Biochem Biophys Res Commun. 2000;268(2):405-8.

Gómez-Ambrosi J, Salvador J, Rotellar F, Silva C, Catalán V, Rodríguez A, et al. Increased serum amyloid A concentrations in morbid obesity decrease after gastric bypass. Obes Surg. 2006;16(3):262-9.

Gorden A, Osman I, Gai W, He D, Huang W, Davidson A, et al. Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res. 2003;63(14):3955-7.

Grada A, Otero-Vinas M, Prieto-Castrillo F, Obagi Z, Falanga V. Research techniques made simple: analysis of collective cell migration using the wound healing assay. J Invest Dermatol . 2017;137(2):11-16.

Han L, Ma Q, Li J, Liu H, Li W, Ma G, et al. High glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. PLoS One. 2011;6(11):1-7.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.

Hansen MT, Forst B, Cremers N, Quagliata L, Ambartsumian N, Grum-Schwensen B, et al. A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4. Oncogene. 2015;34(4):424-35.

Heppt MV, Roesch A, Weide B, Gutzmer R, Meier F, Loquai C, et al. Prognostic Factors and Treatment Outcomes in 444 Patients With Mucosal Melanoma. Eur J Cancer (Oxford, England : 1990). 2017;81:36-44.

Hilmi C, Larribere L, Giuliano S, Bille K, Ortonne JP, Ballotti R, et al. IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin. J Invest Dermatol . 2008;128(6):1499-505.

Hocker TL, Singh MK, Tsao H. Melanoma genetics and therapeutic approaches in the 21st century: moving from the benchside to the bedside. J Invest Dermatol . 2008;128(11):2575-95.

Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose Expression of Tumor Necrosis Factor-Alpha: Direct Role in Obesity-Linked Insulin Resistance. Science (New York, NY). 1993;259(5091):87-91.

Katerinaki E, Evans GS, Lorigan PC, MacNeil S. TNF-alpha increases human melanoma cell invasion and migration in vitro: the role of proteolytic enzymes. Brit J Cancer. 2003;89(6):1123-9.

Kern L, Mittenbühler MJ, Vesting AJ, Ostermann AL, Wunderlich CM, Wunderlich FT. Obesity-induced TNFα and IL-6 Signaling: The missing link between obesity and inflammation-Driven liver and colorectal cancers. Cancers (Basel). 2018;11(1):1-21.

Kim CS, Park HS, Kawada T, Kim JH, Lim D, Hubbard NE, et al. Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (Lond) . 2006;30(9):1347-55.

Klein-Platat C, Drai J, Oujaa M, Schlienger JL, Simon C. Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents. Am J Clin Nutr. 2005;82(6):1178-84.

Labrie F, Luu-The V, Labrie C, Pelletier G, El-Alfy M. Intracrinology and the skin. Horm Res. 2000;54(5-6):218-29.

Lamarre NS, Sr MRR, Braverman AS, Gerstein MI, Mydlo JH. Effect of Obese and Lean Zucker Rat Sera on Human and Rat Prostate Cancer Cells: Implications in Obesity-Related Prostate Tumor Biology. Urology. 2007;69(1):191-195.

Lappalainen T, Kolehmainen M, Schwab U, Pulkkinen L, Laaksonen DE, Rauramaa R, et al. Serum concentrations and expressions of serum amyloid A and leptin in adipose tissue are interrelated: the Genobin Study. Eur J Endocrinol. 2008;158(3):333-41.

Maachi M, Piéroni L, Bruckert E, Jardel C, Fellahi S, Hainque B, et al. Systemic low-grade inflammation is related to both circulating and adipose tissue TNFalpha, leptin and IL-6 levels in obese women. Int J Obes Relat Metab Disord. 2004;28(8):993-7.

Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet . 2010;375(9715):673-85.

Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature . 2008;454(7203):436-44.

Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005;23(4):344-6.

Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549-55.

Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med. 1999;5(7):828-31.

Mueller MM. Inflammation in epithelial skin tumours: old stories and new ideas. Eur J Cancer. 2006;42(6):735-44.

Nissan MH, Pratilas CA, Jones AM, Ramirez R, Won H, Liu C, et al. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res. 2014;74(8):2340-50.

Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M, et al. Leptin and High Glucose Stimulate Cell Proliferation in MCF-7 Human Breast Cancer Cells: Reciprocal Involvement of PKC-alpha and PPAR Expression. Biochim Biophys Acta. 2002;1592(2):107-16.

Palmieri G, Ombra M, Colombino M, Casula M, Sini M, Manca A, et al. Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets. Front Oncol. 2015;5:1-16.

Price RS, Cavazos DA, Angel RED, Hursting SD, deGraffenried LA. Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells. Prostate Cancer and Prostatic Diseases. 2012;15(2):135-43.

Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39-51.

Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423-37.

Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet . 2008;371(9612):569-78.

Ribas A, Flaherty KT. BRAF targeted therapy changes the treatment paradigm in melanoma. Nat Rev Clin Oncol. 2011;8(7):426-33.

Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med. 2010;61:301-16.

Rossi JM, Galon J, Turcan S, Danan C, Locke FL, Neelapu SS, et al. Abstract LB-016: Characteristics of the pretreatment tumor microenvironment may influence clinical response in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi-cel) in the pivotal ZUMA-1. Cancer Research,. 2018;78(13 Supplement): p. LB-016- LB-016.

Rueden CT, Schindelin J, Hiner MC, DeZonia BE, Walter AE, Arena ET, et al. ImageJ2: ImageJ for the next generation of scientific image data. BMC Bioinf. 2017;18(1):1-26.

Rundhaug JE, Fischer SM. Molecular mechanisms of mouse skin tumor promotion. Cancers (Basel). 2010;2(2):436-82.

Ryan MB, Finn AJ, Pedone KH, Thomas NE, Der CJ, Cox AD. ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- And NRAS-Mutant Melanoma. Mol Cancer Res. 2016;14(10):1009-1018.

Sergentanis TN, Antoniadis AG, Gogas HJ, Antonopoulos CN, Adami HO, Ekbom A, et al. Obesity and risk of malignant melanoma: a meta-analysis of cohort and case- control studies. Eur J Cancer . 2013;49(3):642-57.

Sharma SD, Katiyar SK. Leptin deficiency-induced obesity exacerbates ultraviolet B radiation-induced cyclooxygenase-2 expression and cell survival signals in ultraviolet B-irradiated mouse skin. Toxicol Appl Pharmacol. 2010;244(3):328-35.

Sheen YS, Liao YH, Liau JY, Lin MH, Hsieh YC, Jee SH, et al. Prevalence of BRAF and NRAS mutations in cutaneous melanoma patients in Taiwan. J Formos Med Assoc. 2016;115(2):121-7.

Sica A, Schioppa T, Mantovani A, Allavena P. Tumour- associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer . 2006;42(6):717-27.

Uguen A, Talagas M, Costa S, Samaison L, Paule L, Alavi Z, et al. NRAS (Q61R), BRAF (V600E) immunohistochemistry: a concomitant tool for mutation screening in melanomas. Diagn Pathol. 2015;10:121-131.

Volkova E, Robinson BA, Willis J, Currie MJ, Dachs GU. Marginal effects of glucose, insulin and insulin-like growth factor on chemotherapy response in endothelial and colorectal cancer cells. Oncol Lett. 2014;7(2):311-20.

Vona-Davis L, Rose DP. Angiogenesis, adipokines and breast cancer. Cytokine Growth Factor Rev. 2009;20(3):193-201.

Wellbrock C, Karasarides M, Marais R. The RAF Proteins Take Centre Stage. Nat Rev Mol Cell Biol. 2004;5(11):875- 85.

Whitwam T, Vanbrocklin MW, Russo ME, Haak PT, Bilgili D, Resau JH, et al. Differential Oncogenic Potential of Activated RAS Isoforms in Melanocytes. Oncogene . 2007;26(31):4563-70.

Wolin KY, Colditz GA. Can weight loss prevent cancer? Br J Cancer. 2008;99(7):995-9.

Wu Y, Potempa LA, Kebir DE, Filep JG. C-reactive protein and inflammation: conformational changes affect function. Biol Chem. 2015;396(11):1181-1197.

Yamada T. [Serum amyloid A (SAA)-pathogenicity and implication of appearance in plasma]. Rinsho Byori. 2006;54(5):509-12.

Yamada T. Serum amyloid A (SAA): a concise review of biology, assay methods and clinical usefulness. Clin Chem Lab Med. 1999;37(4):381-8.

Zhang Y, Daquinag A, Traktuev DO, Amaya-Manzanares F, Simmons PJ, March KL, et al. White adipose tissue cells are recruited by experimental tumors and promote cancer progression in mouse models. Cancer Res. 2009;69(12):5259- 66.

Zhu N, Lalla R, Eves P, Brown TLH, King A, Kemp EH, et al. Melanoma cell migration is upregulated by tumour necrosis factor-alpha and suppressed by alpha-melanocyte- stimulating hormone. Br J Cancer . 2004;90(7):1457-63.

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Published

2022-12-19

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Original Article

How to Cite

Serum from morbidly obese patients affects melanoma cell behavior in vitro. (2022). Brazilian Journal of Pharmaceutical Sciences, 58. https://doi.org/10.1590/s2175-979020201000X42e19375