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Erschienen in: Cancer Microenvironment 1/2012

01.04.2012 | Original Paper

Adipocytes Promote B16BL6 Melanoma Cell Invasion and the Epithelial-to-Mesenchymal Transition

verfasst von: Kyoko Kushiro, Randy A. Chu, Akanksha Verma, Nomelí P. Núñez

Erschienen in: Cancer Microenvironment | Ausgabe 1/2012

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Abstract

Metastatic melanoma is one of the most deadly and evasive types of cancer. On average, cancer patients with metastatic melanoma survive only 6–9 months after diagnosis. Epidemiological and animal studies suggest that obesity increases the metastatic ability of malignant melanoma, though the mechanism is not known. In the present studies, we assessed the ability of 3T3L1 adipocytes to modulate B16BL6 melanoma cell invasion and the Epithelial-to-Mesenchymal Transition (EMT). For this purpose, we induced the differentiation of 3T3L1 fibroblasts to adipocytes. Then, we collected the cell culture media from both fibroblasts and adipocytes and determined their effect on the invasive ability and EMT gene expression of B16BL6 melanoma cells. Results show that adipocyte media increased that ability of B16BL6 cells to invade. The higher invasive ability of B16BL6 melanoma cells was associated with increased expression of EMT genes such as Snai1, MMP9, Twist, and Vimentin. Additionally, the expression of the cell-to-cell adhesion protein E-cadherin and the metastasis suppressor gene Kiss1 were down-regulated in these B16BL6 cells. Also, adipocytes had high levels of the pro-inflammatory cytokine Interleukin 6 (IL-6). Treatment of B16BL6 cells with IL-6 elicited similar effects as the adipocyte media; IL-6 promoted the invasive ability of B16BL6 melanoma cells, increased the expression of Snai1, and decreased Kiss1 expression. IL-6 neutralization, however, did not have a visible effect on adipocyte media-induced invasion and snai1 staining. In summary, adipocytes may increase the invasive ability of B16BL6 melanoma cells by promoting EMT and decreasing the expression of genes such as E-cadherin and Kiss1.
Literatur
1.
Zurück zum Zitat American Cancer Society. Cancer Facts and Figures (2009) Atlanta, Georgia 2009 American Cancer Society. Cancer Facts and Figures (2009) Atlanta, Georgia 2009
2.
Zurück zum Zitat Klimek VM, Wolchok JD, Chapman PB et al (2000) Systemic chemotherapy. Clin Plast Surg 27(3):451–61, ix–xPubMed Klimek VM, Wolchok JD, Chapman PB et al (2000) Systemic chemotherapy. Clin Plast Surg 27(3):451–61, ix–xPubMed
3.
Zurück zum Zitat Samanic C, Chow W, Gridley G et al (2006) Relation of body mass index to cancer risk in 362,552 Swedish men. Canc Causes Contr 17(7):901–9CrossRef Samanic C, Chow W, Gridley G et al (2006) Relation of body mass index to cancer risk in 362,552 Swedish men. Canc Causes Contr 17(7):901–9CrossRef
4.
Zurück zum Zitat Mori A, Sakurai H, Choo M et al (2006) Severe pulmonary metastasis in obese and diabetic mice. Int J Canc 119(12):2760–7CrossRef Mori A, Sakurai H, Choo M et al (2006) Severe pulmonary metastasis in obese and diabetic mice. Int J Canc 119(12):2760–7CrossRef
5.
Zurück zum Zitat Centers for Disease Control and prevention. Overweight and Obesity. 2009 Centers for Disease Control and prevention. Overweight and Obesity. 2009
6.
Zurück zum Zitat Balistreri CR, Caruso C, Candore G (2010) The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediat Inflamm 2010:802078CrossRef Balistreri CR, Caruso C, Candore G (2010) The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediat Inflamm 2010:802078CrossRef
7.
8.
Zurück zum Zitat Dennis L, Lowe J, Lynch C et al (2008) Cutaneous melanoma and obesity in the Agricultural Health Study. Ann Epidemiol 18(3):214–21PubMedCrossRef Dennis L, Lowe J, Lynch C et al (2008) Cutaneous melanoma and obesity in the Agricultural Health Study. Ann Epidemiol 18(3):214–21PubMedCrossRef
9.
Zurück zum Zitat Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10(4):369–73PubMedCrossRef Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10(4):369–73PubMedCrossRef
10.
Zurück zum Zitat Xing F, Saidou J, Watabe K (2010) Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci 15:166–79PubMedCrossRef Xing F, Saidou J, Watabe K (2010) Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci 15:166–79PubMedCrossRef
11.
Zurück zum Zitat Stout RD, Watkins SK, Suttles J (2009) Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol 86(5):1105–9PubMedCrossRef Stout RD, Watkins SK, Suttles J (2009) Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol 86(5):1105–9PubMedCrossRef
12.
Zurück zum Zitat Siveen KS, Kuttan G (2009) Role of macrophages in tumour progression. Immunol Lett 123(2):97–102PubMedCrossRef Siveen KS, Kuttan G (2009) Role of macrophages in tumour progression. Immunol Lett 123(2):97–102PubMedCrossRef
13.
Zurück zum Zitat Guise T (2010) Examining the metastatic niche: targeting the microenvironment. Semin Oncol 37(Suppl 2):S2–14PubMedCrossRef Guise T (2010) Examining the metastatic niche: targeting the microenvironment. Semin Oncol 37(Suppl 2):S2–14PubMedCrossRef
14.
Zurück zum Zitat Coghlin C, Murray GI (2010) Current and emerging concepts in tumour metastasis. J Pathol 222(1):1–15PubMedCrossRef Coghlin C, Murray GI (2010) Current and emerging concepts in tumour metastasis. J Pathol 222(1):1–15PubMedCrossRef
15.
Zurück zum Zitat Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–64PubMedCrossRef Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–64PubMedCrossRef
16.
Zurück zum Zitat Bonnomet A, Brysse A, Tachsidis A et al (2010) Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary Gland Biol Neoplasia 15(2):261–73PubMedCrossRef Bonnomet A, Brysse A, Tachsidis A et al (2010) Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary Gland Biol Neoplasia 15(2):261–73PubMedCrossRef
17.
Zurück zum Zitat Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Canc 7(6):415–28CrossRef Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Canc 7(6):415–28CrossRef
18.
Zurück zum Zitat Kang Y, Massagué J (2004) Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118(3):277–9PubMedCrossRef Kang Y, Massagué J (2004) Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118(3):277–9PubMedCrossRef
19.
Zurück zum Zitat Yang J, Mani SA, Donaher JL et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–39PubMedCrossRef Yang J, Mani SA, Donaher JL et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–39PubMedCrossRef
20.
Zurück zum Zitat Przybylo JA, Radisky DC (2007) Matrix metalloproteinase-induced epithelial-mesenchymal transition: tumor progression at Snail’s pace. Int J Biochem Cell Biol 39(6):1082–8PubMedCrossRef Przybylo JA, Radisky DC (2007) Matrix metalloproteinase-induced epithelial-mesenchymal transition: tumor progression at Snail’s pace. Int J Biochem Cell Biol 39(6):1082–8PubMedCrossRef
21.
Zurück zum Zitat Dissanayake SK, Wade M, Johnson CE et al (2007) The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem 282(23):17259–71PubMedCrossRef Dissanayake SK, Wade M, Johnson CE et al (2007) The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem 282(23):17259–71PubMedCrossRef
22.
Zurück zum Zitat Steeg P (2003) Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Canc 3(1):55–63CrossRef Steeg P (2003) Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Canc 3(1):55–63CrossRef
23.
Zurück zum Zitat Stafford L, Vaidya K, Welch D (2008) Metastasis suppressors genes in cancer. Int J Biochem Cell Biol 40(5):874–91PubMedCrossRef Stafford L, Vaidya K, Welch D (2008) Metastasis suppressors genes in cancer. Int J Biochem Cell Biol 40(5):874–91PubMedCrossRef
24.
Zurück zum Zitat Thiery J, Acloque H, Huang R et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–90PubMedCrossRef Thiery J, Acloque H, Huang R et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–90PubMedCrossRef
25.
Zurück zum Zitat Sadowski HB, Wheeler TT, Young DA (1992) Gene expression during 3T3-L1 adipocyte differentiation. Characterization of initial responses to the inducing agents and changes during commitment to differentiation. J Biol Chem 267(7):4722–31PubMed Sadowski HB, Wheeler TT, Young DA (1992) Gene expression during 3T3-L1 adipocyte differentiation. Characterization of initial responses to the inducing agents and changes during commitment to differentiation. J Biol Chem 267(7):4722–31PubMed
26.
Zurück zum Zitat Wu Z, Xie Y, Morrison RF et al (1998) PPARgamma induces the insulin-dependent glucose transporter GLUT4 in the absence of C/EBPalpha during the conversion of 3T3 fibroblasts into adipocytes. J Clin Invest 101(1):22–32PubMedCrossRef Wu Z, Xie Y, Morrison RF et al (1998) PPARgamma induces the insulin-dependent glucose transporter GLUT4 in the absence of C/EBPalpha during the conversion of 3T3 fibroblasts into adipocytes. J Clin Invest 101(1):22–32PubMedCrossRef
27.
Zurück zum Zitat Ansieau S, Morel AP, Hinkal G et al (2010) TWISTing an embryonic transcription factor into an oncoprotein. Oncogene 29(22):3173–84PubMedCrossRef Ansieau S, Morel AP, Hinkal G et al (2010) TWISTing an embryonic transcription factor into an oncoprotein. Oncogene 29(22):3173–84PubMedCrossRef
28.
Zurück zum Zitat Sullivan N, Sasser A, Axel A et al (2009) Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28(33):2940–7PubMedCrossRef Sullivan N, Sasser A, Axel A et al (2009) Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28(33):2940–7PubMedCrossRef
29.
Zurück zum Zitat Wu Y, Deng J, Rychahou P et al (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Canc Cell 15(5):416–28CrossRef Wu Y, Deng J, Rychahou P et al (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Canc Cell 15(5):416–28CrossRef
30.
Zurück zum Zitat Kuphal S, Palm HG, Poser I et al (2005) Snail-regulated genes in malignant melanoma. Melanoma Res 15(4):305–13PubMedCrossRef Kuphal S, Palm HG, Poser I et al (2005) Snail-regulated genes in malignant melanoma. Melanoma Res 15(4):305–13PubMedCrossRef
31.
Zurück zum Zitat Alonso SR, Tracey L, Ortiz P et al (2007) A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis. Canc Res 67(7):3450–60CrossRef Alonso SR, Tracey L, Ortiz P et al (2007) A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis. Canc Res 67(7):3450–60CrossRef
32.
Zurück zum Zitat Tse JC, Kalluri R (2007) Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 101(4):816–29PubMedCrossRef Tse JC, Kalluri R (2007) Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 101(4):816–29PubMedCrossRef
33.
Zurück zum Zitat Pećina-Slaus N (2003) Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Canc Cell Int 3(1):17CrossRef Pećina-Slaus N (2003) Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Canc Cell Int 3(1):17CrossRef
34.
Zurück zum Zitat Vesuna F, van Diest P, Chen JH et al (2008) Twist is a transcriptional repressor of E-cadherin gene expression in breast cancer. Biochem Biophys Res Commun 367(2):235–41PubMedCrossRef Vesuna F, van Diest P, Chen JH et al (2008) Twist is a transcriptional repressor of E-cadherin gene expression in breast cancer. Biochem Biophys Res Commun 367(2):235–41PubMedCrossRef
35.
Zurück zum Zitat Jordà M, Olmeda D, Vinyals A et al (2005) Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci 118(Pt 15):3371–85PubMedCrossRef Jordà M, Olmeda D, Vinyals A et al (2005) Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci 118(Pt 15):3371–85PubMedCrossRef
36.
Zurück zum Zitat Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67PubMedCrossRef Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67PubMedCrossRef
37.
Zurück zum Zitat Lee J, Miele M, Hicks D et al (1996) KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 88(23):1731–7PubMedCrossRef Lee J, Miele M, Hicks D et al (1996) KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 88(23):1731–7PubMedCrossRef
38.
Zurück zum Zitat Yan C, Wang H, Boyd D (2001) KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-kappa B binding to the promoter as a consequence of Ikappa Balpha -induced block of p65/p50 nuclear translocation. J Biol Chem 276(2):1164–72PubMedCrossRef Yan C, Wang H, Boyd D (2001) KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-kappa B binding to the promoter as a consequence of Ikappa Balpha -induced block of p65/p50 nuclear translocation. J Biol Chem 276(2):1164–72PubMedCrossRef
39.
Zurück zum Zitat Taylor MA, Parvani JG, Schiemann WP (2010) The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells. J Mammary Gland Biol Neoplasia 15(2):169–90PubMedCrossRef Taylor MA, Parvani JG, Schiemann WP (2010) The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells. J Mammary Gland Biol Neoplasia 15(2):169–90PubMedCrossRef
40.
Zurück zum Zitat Miyazono K (2009) Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci 85(8):314–23PubMedCrossRef Miyazono K (2009) Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci 85(8):314–23PubMedCrossRef
41.
Zurück zum Zitat Xu J, Lamouille S, Derynck R (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19(2):156–72PubMedCrossRef Xu J, Lamouille S, Derynck R (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19(2):156–72PubMedCrossRef
42.
Zurück zum Zitat Bortell R, Owen TA, Ignotz R et al (1994) TGF beta 1 prevents the down-regulation of type I procollagen, fibronectin, and TGF beta 1 gene expression associated with 3T3-L1 pre-adipocyte differentiation. J Cell Biochem 54(2):256–63PubMedCrossRef Bortell R, Owen TA, Ignotz R et al (1994) TGF beta 1 prevents the down-regulation of type I procollagen, fibronectin, and TGF beta 1 gene expression associated with 3T3-L1 pre-adipocyte differentiation. J Cell Biochem 54(2):256–63PubMedCrossRef
43.
Zurück zum Zitat Samad F, Yamamoto K, Pandey M et al (1997) Elevated expression of transforming growth factor-beta in adipose tissue from obese mice. Mol Med 3(1):37–48PubMed Samad F, Yamamoto K, Pandey M et al (1997) Elevated expression of transforming growth factor-beta in adipose tissue from obese mice. Mol Med 3(1):37–48PubMed
44.
Zurück zum Zitat Samad F, Uysal KT, Wiesbrock SM et al (1999) Tumor necrosis factor alpha is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. Proc Natl Acad Sci USA 96(12):6902–7PubMedCrossRef Samad F, Uysal KT, Wiesbrock SM et al (1999) Tumor necrosis factor alpha is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. Proc Natl Acad Sci USA 96(12):6902–7PubMedCrossRef
45.
Zurück zum Zitat Fu H, Hu Z, Wen J et al (2009) TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. Acta Biochim Biophys Sin (Shanghai) 41(8):648–56CrossRef Fu H, Hu Z, Wen J et al (2009) TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. Acta Biochim Biophys Sin (Shanghai) 41(8):648–56CrossRef
46.
Zurück zum Zitat Yao Z, Fenoglio S, Gao DC et al (2010) TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci USA 107(35):15535–40PubMedCrossRef Yao Z, Fenoglio S, Gao DC et al (2010) TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci USA 107(35):15535–40PubMedCrossRef
Metadaten
Titel
Adipocytes Promote B16BL6 Melanoma Cell Invasion and the Epithelial-to-Mesenchymal Transition
verfasst von
Kyoko Kushiro
Randy A. Chu
Akanksha Verma
Nomelí P. Núñez
Publikationsdatum
01.04.2012
Verlag
Springer Netherlands
Erschienen in
Cancer Microenvironment / Ausgabe 1/2012
Print ISSN: 1875-2292
Elektronische ISSN: 1875-2284
DOI
https://doi.org/10.1007/s12307-011-0087-2

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