Skip to main content

Advertisement

SpringerLink
Log in

Melanoma and the tumor microenvironment

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Melanoma arises through the accrual of mutations in genes critical for proliferation and survival. Although melanoma had been traditionally conceptualized as a cell-autonomous event, increasing evidence supports the notion that these tumors are not isolated entities but rather depend, interact with, and react to the adjacent microenvironment. Melanoma is composed of not only the malignant cells but also the supporting stroma, which includes fibroblasts, endothelial cells, immune cells, soluble molecules, and the extracellular matrix (ECM). Tumor cells actively interact with the microenvironment in a bidirectional manner through molecular signals that modulate the malignant phenotype. This article briefly reviews the molecular basis of melanomagenesis as well as the interplay of melanoma with other cells of the tumor microenvironment and components of the ECM. It also discusses the influence of the microenvironment on therapeutic targeting of melanoma, highlighting recent studies that propose novel strategies to target tumor-microenvironment interactions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Tawbi HA, Kirkwood JM: Management of metastatic melanoma. Semin Oncol 2007, 34:532–545.

    Article  PubMed  CAS  Google Scholar 

  2. Smalley KS, Lioni M, Noma K, et al.: In vitro three-dimensional tumor microenvironment models for anticancer drug discovery. Expert Opin Drug Discov 2008, 3:1–10.

    Article  CAS  Google Scholar 

  3. Haass NK, Smalley KS, Li L, et al.: Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res 2005, 18:150–159.

    Article  PubMed  CAS  Google Scholar 

  4. Meier F, Schittek B, Busch S, et al.: The RAS/RAF/MEK/ERK and PI3K/AKT signaling pathways present molecular targets for the effective treatment of advanced melanoma. Front Biosci 2005, 10:2986–3001.

    Article  PubMed  CAS  Google Scholar 

  5. Li G, Fukunaga M, Herlyn M: Reversal of melanocytic malignancy by keratinocytes is an E-cadherin-mediated process overriding beta-catenin signaling. Exp Cell Res 2004, 297:142–151.

    Article  PubMed  CAS  Google Scholar 

  6. Hsu MY, Meier F, Herlyn M: Melanoma development and progression: a conspiracy between tumor and host. Differentiation 2002, 70:522–536.

    Article  PubMed  CAS  Google Scholar 

  7. Gottardi CJ, Wong E, Gumbiner BM: E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J Cell Biol 2001, 153:1049–1060.

    Article  PubMed  CAS  Google Scholar 

  8. Li G, Satyamoorthy K, Herlyn M: N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res 2001, 61:3819–3825.

    PubMed  CAS  Google Scholar 

  9. Larue L, Delmas V: The WNT/beta-catenin pathway in melanoma. Front Biosci 2006, 11:733–742.

    Article  PubMed  CAS  Google Scholar 

  10. Widlund HR, Horstmann MA, Price ER, et al.: Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor. J Cell Biol 2002, 158:1079–1087.

    Article  PubMed  CAS  Google Scholar 

  11. Delmas V, Beermann F, Martinozzi S, et al.: Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes Dev 2007, 21:2923–2935.

    Article  PubMed  CAS  Google Scholar 

  12. Bolos V, Peinado H, Perez-Moreno MA, et al.: The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci 2003, 116:499–511.

    Article  PubMed  CAS  Google Scholar 

  13. Conacci-Sorrell M, Simcha I, Ben-Yedidia T, et al.: Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J Cell Biol 2003, 163:847–857.

    Article  PubMed  CAS  Google Scholar 

  14. Poser I, Dominguez D, de Herreros AG, et al.: Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem 2001, 276:24661–24666.

    Article  PubMed  CAS  Google Scholar 

  15. Li G, Schaider H, Satyamoorthy K, et al.: Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene 2001, 20:8125–8135.

    Article  PubMed  CAS  Google Scholar 

  16. Smit DJ, Gardiner BB, Sturm RA: Osteonectin downregulates E-cadherin, induces osteopontin and focal adhesion kinase activity stimulating an invasive melanoma phenotype. Int J Cancer 2007, 121:2653–2660.

    Article  PubMed  CAS  Google Scholar 

  17. Moschos SJ, Drogowski LM, Reppert SL, et al.: Integrins and cancer. Oncology (Williston Park) 2007, 21:13–20.

    Google Scholar 

  18. Hess AR, Postovit LM, Margaryan NV, et al.: Focal adhesion kinase promotes the aggressive melanoma phenotype. Cancer Res 2005, 65:9851–9860.

    Article  PubMed  CAS  Google Scholar 

  19. Villanueva J, Yung Y, Walker JL, et al.: ERK activity and G1 phase progression: identifying dispensable versus essential activities and primary versus secondary targets. Mol Biol Cell 2007, 18:1457–1463.

    Article  PubMed  CAS  Google Scholar 

  20. Stupack DG, Cheresh DA: Get a ligand, get a life: integrins, signaling and cell survival. J Cell Sci 2002, 115:3729–3738.

    Article  PubMed  CAS  Google Scholar 

  21. Albelda SM, Mette SA, Elder DE, et al.: Integrin distribution in malignant melanoma: association of the beta 3 subunit with tumor progression. Cancer Res 1990, 50:6757–6764.

    PubMed  CAS  Google Scholar 

  22. Brooks PC, Stromblad S, Sanders LC, et al.: Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 1996, 85:683–693.

    Article  PubMed  CAS  Google Scholar 

  23. Petitclerc E, Stromblad S, von Schalscha TL, et al.: Integrin alpha(v)beta3 promotes M21 melanoma growth in human skin by regulating tumor cell survival. Cancer Res 1999, 59:2724–2730.

    PubMed  CAS  Google Scholar 

  24. Lawler K, Meade G, O’sullivan G, Kenny D: Shear stress modulates the interaction of platelet-secreted matrix proteins with tumor cells through the integrin alphavbeta3. Am J Physiol Cell Physiol 2004, 287:C1320–C1327.

    Article  PubMed  CAS  Google Scholar 

  25. Pilch J, Habermann R, Felding-Habermann B: Unique ability of integrin alpha(v)beta3 to support tumor cell arrest under dynamic flow conditions. J Biol Chem 2002, 277:21930–21938.

    Article  PubMed  CAS  Google Scholar 

  26. Conway WC, Van der Voort van Zyp J, Thamilselvan V, et al.: Paxillin modulates squamous cancer cell adhesion and is important in pressure-augmented adhesion. J Cell Biochem 2006, 98:1507–1516.

    Article  PubMed  CAS  Google Scholar 

  27. Hart IR, Fidler IJ: Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res 1980, 40:2281–2287.

    PubMed  CAS  Google Scholar 

  28. Ruiter D, Bogenrieder T, Elder D, et al.: Melanoma-stroma interactions: structural and functional aspects. Lancet Oncol 2002, 3:35–43.

    Article  PubMed  CAS  Google Scholar 

  29. Labrousse AL, Ntayi C, Hornebeck W, et al.: Stromal reaction in cutaneous melanoma. Crit Rev Oncol Hematol 2004, 49:269–275.

    Article  PubMed  Google Scholar 

  30. Nesbit M, Nesbit HK, Bennett J, et al.: Basic fibroblast growth factor induces a transformed phenotype in normal human melanocytes. Oncogene 1999, 18:6469–6476.

    Article  PubMed  CAS  Google Scholar 

  31. Lazar-Molnar E, Hegyesi H, Toth S, et al.: Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 2000, 12:547–554.

    Article  PubMed  CAS  Google Scholar 

  32. Koprowski H, Herlyn M, Balaban G, et al.: Expression of the receptor for epidermal growth factor correlates with increased dosage of chromosome 7 in malignant melanoma. Somat Cell Mol Genet 1985, 11:297–302.

    Article  PubMed  CAS  Google Scholar 

  33. Bardeesy N, Kim M, Xu J, et al.: Role of epidermal growth factor receptor signaling in RAS-driven melanoma. Mol Cell Biol 2005, 25:4176–4188.

    Article  PubMed  CAS  Google Scholar 

  34. Smalley KS, Brafford PA, Herlyn M: Selective evolutionary pressure from the tissue microenvironment drives tumor progression. Semin Cancer Biol 2005, 15:451–459.

    Article  PubMed  CAS  Google Scholar 

  35. Lee JT, Herlyn M: Microenvironmental influences in melanoma progression. J Cell Biochem 2007, 101:862–872.

    Article  PubMed  CAS  Google Scholar 

  36. Bierie B, Moses HL: Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006, 6:506–520.

    Article  PubMed  CAS  Google Scholar 

  37. Hussein MR: Transforming growth factor-beta and malignant melanoma: molecular mechanisms. J Cutan Pathol 2005, 32:389–395.

    Article  PubMed  Google Scholar 

  38. Berking C, Takemoto R, Schaider H, et al.: Transforming growth factor-beta1 increases survival of human melanoma through stroma remodeling. Cancer Res 2001, 61:8306–8316.

    PubMed  CAS  Google Scholar 

  39. Folkman J: Angiogenesis. Annu Rev Med 2006, 57:1–18.

    Article  PubMed  CAS  Google Scholar 

  40. Mahabeleshwar GH, Byzova TV: Angiogenesis in melanoma. Semin Oncol 2007, 34:555–565.

    Article  PubMed  CAS  Google Scholar 

  41. Fischer C, Jonckx B, Mazzone M, et al.: Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 2007, 131:463–475.

    Article  PubMed  CAS  Google Scholar 

  42. Ugurel S, Rappl G, Tilgen W, et al.: Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. J Clin Oncol 2001, 19:577–583.

    PubMed  CAS  Google Scholar 

  43. Hood JD, Frausto R, Kiosses WB, et al.: Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis. J Cell Biol 2003, 162:933–943.

    Article  PubMed  CAS  Google Scholar 

  44. Hofmann UB, Westphal JR, Van Muijen GN, et al.: Matrix metalloproteinases in human melanoma. J Invest Dermatol 2000, 115:337–344.

    Article  PubMed  CAS  Google Scholar 

  45. Martin MD, Matrisian LM: The other side of MMPs: protective roles in tumor progression. Cancer Metastasis Rev 2007, 26:717–724.

    Article  PubMed  CAS  Google Scholar 

  46. Overall CM, Kleifeld O: Tumour microenvironment — opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 2006, 6:227–239.

    Article  PubMed  CAS  Google Scholar 

  47. King J, Zhao J, Clingan P, et al.: Randomised double blind placebo control study of adjuvant treatment with the metalloproteinase inhibitor, Marimastat in patients with inoperable colorectal hepatic metastases: significant survival advantage in patients with musculoskeletal side-effects. Anticancer Res 2003, 23:639–645.

    PubMed  CAS  Google Scholar 

  48. Palermo C, Joyce JA: Cysteine cathepsin proteases as pharmacological targets in cancer. Trends Pharmacol Sci 2008, 29:22–28.

    Article  PubMed  CAS  Google Scholar 

  49. 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 2008, 23:225–231.

    Article  Google Scholar 

  50. Quintanilla-Dieck MJ, Codriansky K, Keady M, et al.: Cathepsin K in melanoma invasion. J Invest Dermatol 2008, Mar 27 (Epub ahead of print).

Download references

Author information

Authors and Affiliations

  1. The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA

    Meenhard Herlyn

Authors
  1. Jessie Villanueva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meenhard Herlyn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meenhard Herlyn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Villanueva, J., Herlyn, M. Melanoma and the tumor microenvironment. Curr Oncol Rep 10, 439–446 (2008). https://doi.org/10.1007/s11912-008-0067-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-008-0067-y

Keywords

Search

Navigation