Skip to main content

Advertisement

SpringerLink
Log in

Pilot Study on “Pericytic Mimicry” and Potential Embryonic/Stem Cell Properties of Angiotropic Melanoma Cells Interacting with the Abluminal Vascular Surface

  • Original Paper
  • Published:
Cancer Microenvironment

Abstract

The interaction of tumor cells with the tumor vasculature is mainly studied for its role in tumor angiogenesis and intravascular metastasis of circulating tumor cells. In addition, a specific interaction of tumor cells with the abluminal surfaces of vessels, or angiotropism, may promote the migration of angiotropic tumor cells along the abluminal vascular surfaces in a pericytic location. This process has been termed extravascular migratory metastasis. The abluminal vascular surface may also provide a vascular niche inducing or sustaining stemness to angiotropic tumor cells. This pilot study investigated if angiotropic melanoma cells might represent a subset population with pericytic and embryonic or stem cell properties. Through microarray analysis, we showed that the interaction between melanoma cells and the abluminal surface of endothelial cells triggers significant differential expression of several genes. The most significantly differentially expressed genes have demonstrated properties linked to cancer cell migration (CCL2, ICAM1 and IL6), cancer progression (CCL2, ICAM1, SELE, TRAF1, IL6, SERPINB2 and CXCL6), epithelial to mesenchymal transition (CCL2 and IL6), embryonic/stem cell properties (CCL2, PDGFB, EVX1 and CFDP1) and pericytic recruitment (PDGFB). In addition, bioinformatics-based analysis of the differentially expressed genes has shown that the most significantly enriched functional groups included development, cell movement, cancer, and embryonic development. Finally, the investigation of pericyte/mesenchymal stem cells markers via immunostaining of human melanoma samples revealed expression of PDGFRB, NG2 and CD146 by angiotropic melanoma cells. Taken together, these preliminary data are supportive of the “pericytic mimicry” by angiotropic melanoma cells, and suggest that the interaction between melanoma cells and the abluminal vascular surface induce differential expression of genes linked to cancer migration and embryonic/stem cell properties.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sitohy B, Nagy JA, Dvorak HF (2012) Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res 72(8):1909–1914

    Article  PubMed  CAS  Google Scholar 

  2. Sleeman JP, Cady B, Pantel K (2012) The connectivity of lymphogenous and hematogenous tumor cell dissemination: biological insights and clinical implications. Clin Exp Metastasis. [Epub ahead of print]

  3. Paterlini-Bréchot P (2011) Organ-specific markers in circulating tumor cell screening: an early indicator of metastasis-capable malignancy. Future Oncol 7(7):849–871

    Article  PubMed  Google Scholar 

  4. Lugassy C, Barnhill RL (2007) Angiotropic malignant melanoma and extravascular migratory metastasis: A review. Adv Anat Pathol 14(3):195–201

    Article  PubMed  Google Scholar 

  5. Van Es SL, Colman M, Thompson JF, McCarthy SW, Scolyer RA (2008) Angiotropism is an independent predictor of local recurrence and in-transit metastasis in primary cutaneous melanoma. Am J Surg Pathol 32(9):1396–1403

    Article  PubMed  Google Scholar 

  6. Wilmott J, Haydu L, Bagot M, Zhang Y, Jakrot V et al. (2012) Angiotropism is an independent predictor of microscopic satellites in primary cutaneous melanoma. Histopathology doi:10.1111/j.1365-2559.2012.04279.x. [Epub ahead of print]

  7. Lugassy C, Kleinman HK, Fernandez PM, Patierno SR, Webber MM, Ghanem G, Spatz A, Barnhill RL (2002) Human melanoma cell migration along capillary-like structures in vitro: A new dynamic model for studying extravascular migratory metastasis. J Invest Dermatol 119(3):703–704

    Article  PubMed  CAS  Google Scholar 

  8. Lugassy C, Kleinman HK, Engbring JA, Welch DR, Harms JF et al (2004) Angiotropism and Pericyte-Like Location of GFP Melanoma Cells:Ex vivo and in vivo studies of Extravascular Migratory Metastasis. Am J Pathol 164:11911198

    Article  Google Scholar 

  9. Lugassy C, Kleinman HK, Vernon SE, Welch DR, Barnhill RL (2007) C16 laminin peptide increases angiotropic extravascular migration of human melanoma cells in a shell-less chick cam assay. Br J Dermatol 157(4):780–782

    Article  PubMed  CAS  Google Scholar 

  10. Levy MJ, Gleeson FC, Zhang L (2009) Endoscopic ultrasound fine-needle aspiration detection of extravascular migratory metastasis from a remotely located pancreatic cancer. Clin Gastroenterol Hepatol 7(2):246–248

    Article  PubMed  Google Scholar 

  11. Takakura N (2012) Formation and regulation of the cancer stem cell niche. Cancer Sci [Epub ahead of print]

  12. Girouard SD, Murphy GF (2011) Melanoma stem cells: not rare, but well done. Lab Invest 91(5):647–664

    Article  PubMed  Google Scholar 

  13. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH et al (2006) Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66:9339–9344

    Article  PubMed  CAS  Google Scholar 

  14. Liu HG, Chen C, Yang H, Pan YF, Zhang XH (2004) Cancer stem cell subsets and their relationships. J Transl Med Genes Dev 18(10):1131–1143

    Google Scholar 

  15. Le Douarin NM, Creuzet S, Couly G, Dupin E (2004) Neural crest cell plasticity and its limits. Development 131:4637–4650

    Article  PubMed  Google Scholar 

  16. Schwarz Q, Maden CH, Vieira JM, Ruhrberg C (2009) Neuropilin 1 signaling guides neural crest cells to coordinate pathway choice with cell specification. PNAS 106:6164–6169

    Article  PubMed  CAS  Google Scholar 

  17. Nagy N, Mwizerwa O, Yaniv K, Carmel L, Pieretti-Vanmarcke R et al (2009) Endothelial cells promote migration and proliferation of enteric neural crest cells via beta1 integrin signaling. Dev Biol 330(2):263–272

    Article  PubMed  CAS  Google Scholar 

  18. Brighton CT, Lorich DG, Kupcha R, Reilly TM, Jones AR, Woodbury RA (1992) The pericyte as a possible osteoblast progenitor cell. Clin Orthop Relat Res 275:287–299

    PubMed  Google Scholar 

  19. Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Canfield AE (1998) Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res 13(5):828–838

    Article  PubMed  CAS  Google Scholar 

  20. Farrington-Rock C, Crofts NJ, Doherty MJ, Ashton BA, Griffin-Jones C, Canfield AE (2004) Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 110(15):2226–2232

    Article  PubMed  CAS  Google Scholar 

  21. Crisan M, Yap S, Casteilla L et al (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3(3):301–313

    Article  PubMed  CAS  Google Scholar 

  22. Welch DR, Bisi JE, Miller BE, Conaway D, Seftor EA et al (1991) Characterization of a highly invasive and spontaneously metastatic human malignant melanoma cell line. Int J Cancer 47(2):227–237

    Article  PubMed  CAS  Google Scholar 

  23. Kubota Y, Kleinman HK, Martin GR, Lawley TJ (1988) Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures. J Cell Biol 107(4):1589–1598

    Article  PubMed  CAS  Google Scholar 

  24. Seftor RE, Hess AR, Seftor EA, Kirschmann DA, Hardy KM et al (2012) Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol 181(4):1115–1125

    Article  PubMed  CAS  Google Scholar 

  25. Benton G, Kleinman HK, George J, Arnaoutova I (2011) Multiple uses of basement membrane-like matrix (BME/Matrigel) in vitro and in vivo with cancer cells. Int J Cancer 128(8):1751–1757

    Article  PubMed  CAS  Google Scholar 

  26. Tang CH, Tsai CC (2012) CCL2 increases MMP-9 expression and cell motility in human chondrosarcoma cells via the Ras/Raf/MEK/ERK/NF-κB signaling pathway. Biochem Pharmacol 83(3):335–344

    Article  PubMed  CAS  Google Scholar 

  27. Loberg RD, Day LL, Harwood J, Ying C, St John LN et al (2006) CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia 8(7):578–586

    Article  PubMed  CAS  Google Scholar 

  28. Chen PC, Lin TH, Cheng HC, Tang CH (2012) CCN3 increases cell motility and ICAM-1 expression in prostate cancer cells. Carcinogenesis 33(4):937–945

    Article  PubMed  CAS  Google Scholar 

  29. Snyder M, Huang XY, Zhang JJ (2011) Signal transducers and activators of transcription 3 (STAT3) directly regulates cytokine-induced fascin expression and is required for breast cancer cell migration. J Biol Chem 286(45):38886–38893

    Article  PubMed  CAS  Google Scholar 

  30. Yu HG, Nam JO, Miller NL, Tanjoni I, Walsh C et al (2011) p190RhoGEF (Rgnef) promotes colon carcinoma tumor progression via interaction with focal adhesion kinase. Cancer Res 71(2):360–370

    Article  PubMed  CAS  Google Scholar 

  31. Suresh B, Ramakrishna S, Kim YS, Kim SM, Kim MS et al (2010) Stability and function of mammalian lethal giant larvae-1 oncoprotein are regulated by the scaffolding protein RanBPM. J Biol Chem 285(46):35340–35349

    Article  PubMed  CAS  Google Scholar 

  32. Soria G, Ben-Baruch A (2008) The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett 267(2):271–285

    Article  PubMed  CAS  Google Scholar 

  33. Wai Wong C, Dye DE, Coombe DR (2012) The role of immunoglobulin superfamily cell adhesion molecules in cancer metastasis. Int J Cell Biol 2012:340296

    PubMed  Google Scholar 

  34. Natali PG, Hamby CV, Felding-Habermann B, Liang B, Nicotra MR et al (1997) Clinical significance of alpha(v) beta3 integrin and intercellular adhesion molecule-1 expression in cutaneous malignant melanoma lesions. Cancer Res 57(8):1554–1560

    PubMed  CAS  Google Scholar 

  35. Witz IP (2008) The selectin-selectin ligand axis in tumor progression. Cancer Metastasis Rev 1:19–30, Review

    Article  Google Scholar 

  36. Yamaoka T, Fujimoto M, Ogawa F, Yoshizaki A, Bae SJ et al (2011) The roles of P- and E-selectins and P-selectin glycoprotein ligand-1 in primary and metastatic mouse melanomas. J Dermatol Sci 2:99–107

    Article  Google Scholar 

  37. Yang L, Gu L, Li Z, Zhou M (2010) Translation of TRAF1 is regulated by IRES-dependent mechanism and stimulated by vincristine. Nucleic Acids Res 38(13):4503–4513

    Article  PubMed  CAS  Google Scholar 

  38. Croucher DR, Saunders DN, Lobov S, Ranson M (2008) Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat Rev Cancer 7:535–545

    Article  Google Scholar 

  39. Verbeke H, Struyf S, Berghmans N, Van Coillie E, Opdenakker G (2011) Isotypic neutralizing antibodies against mouse GCP-2/CXCL6 inhibit melanoma growth and metastasis. Cancer Lett 302(1):54–62

    Article  PubMed  CAS  Google Scholar 

  40. Cavalli LR, Noone AM, Makambi KH, Rone JD, Kasid UN (2011) Frequent loss of the BLID gene in early-onset breast cancer. Cytogenet Genome Res 135(1):19–24

    Article  PubMed  CAS  Google Scholar 

  41. Kirchhofer D, Vucic D (2012) Protease activity of MALT1: a mystery unravelled. Biochem J 444(2):e3–e5

    Article  PubMed  CAS  Google Scholar 

  42. Wang D, Zavadil J, Martin L, Parisi F, Friedman E (2011) Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis. Mol Cell Biol 17:3670–3680

    Article  Google Scholar 

  43. Zhang F, Suarez G, Sha J, Sierra JC, Peterson JW (2009) Phospholipase A2-activating protein (PLAA) enhances cisplatin-induced apoptosis in HeLa cells. Cell Signal 7:1085–1099

    Article  Google Scholar 

  44. Kuramitsu Y, Hayashi E, Okada F, Tanaka T, Zhang X (2010) Proteomic analysis for nuclear proteins related to tumour malignant progression: a comparative proteomic study between malignant progressive cells and regressive cells. Anticancer Res 30(6):2093–2099

    PubMed  CAS  Google Scholar 

  45. Soria G, Ofri-Shahak M, Haas I, Yaal-Hahoshen N, Leider-Trejo L (2011) Inflammatory mediators in breast cancer: coordinated expression of TNFα & IL-1β with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition. BMC Cancer 11:130

    Article  PubMed  CAS  Google Scholar 

  46. Tamura Y, Matsumura K, Sano M, Tabata H, Kimura K (2011) Neural crest-derived stem cells migrate and differentiate into cardiomyocytes after myocardial infarction. Arterioscler Thromb Vasc Biol 31(3):582–589

    Article  PubMed  CAS  Google Scholar 

  47. Tsuyada A, Chow A, Wu J, Somlo G, Chu P (2012) CCL2 Mediates crosstalk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res [Epub ahead of print]

  48. Andjelkovic AV, Song L, Dzenko KA, Cong H, Pachter JS (2002) Functional expression of CCR2 by human fetal astrocytes. J Neurosci Res 70(2):219–231

    Article  PubMed  CAS  Google Scholar 

  49. Jiang Y, Boije M, Westermark B, Uhrbom L (2011) PDGF-B Can sustain self-renewal and tumorigenicity of experimental glioma-derived cancer-initiating cells by preventing oligodendrocyte differentiation. Neoplasia 6:492–503

    Google Scholar 

  50. Kalisz M, Winzi M, Bisgaard HC, Serup P (2012) EVEN-SKIPPED HOMEOBOX 1 controls human ES cell differentiation by directly repressing GOOSECOID expression. Dev Biol 362(1):94–103

    Article  PubMed  CAS  Google Scholar 

  51. Ito Y, Zhang Y, Dangaria S, Luan X, Diekwisch TG (2011) NF-Y and USF1 transcription factor binding to CCAAT-box and E-box elements activates the CP27 promoter. Gene 473(2):92–99

    Article  PubMed  CAS  Google Scholar 

  52. Chang Y, Paramasivam M, Girgenti MJ, Walikonis RS, Bianchi E (2010) RanBPM regulates the progression of neuronal precursors through M-phase at the surface of the neocortical ventricular zone. Dev Neurobiol 70(1):1–15

    PubMed  CAS  Google Scholar 

  53. Armulik A, Abramsson A, Betsholtz C (2005) Pericyte recruitment during angiogenesis. Circ Res 97(6):512–523

    Article  PubMed  CAS  Google Scholar 

  54. McGary EC, Onn A, Mills L, Heimberger A, Eton O et al (2004) Imatinib mesylate inhibits platelet-derived growth factor receptor phosphorylation of melanoma cells but does not affect tumorigenicity in vivo. J Invest Dermatol 122(2):400–405

    Article  PubMed  CAS  Google Scholar 

  55. Shi H, Kong X, Ribas A, Lo RS (2011) Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res 71(15):5067–5074

    Article  PubMed  CAS  Google Scholar 

  56. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM et al (2008) Identification of cells initiating human melanomas. Nature 451(7176):345–349

    Article  PubMed  CAS  Google Scholar 

  57. Boiko AD, Razorenova OV, van de Rijn M, Swetter SM, Johnson DL et al (2010) Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 466(7302):133–137

    Article  PubMed  CAS  Google Scholar 

  58. La Porta CA, Zapperi S (2012) Human breast and melanoma cancer stem cells biomarkers. Cancer Lett [Epub ahead of print]

  59. Quintana E, Shackleton M, Foster HR, Fullen DR, Sabel MS et al (2010) Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18(5):510–523

    Article  PubMed  CAS  Google Scholar 

  60. Bailey CM, Morrison JA, Kulesa PM (2012) Melanoma revives an embryonic migration program to promote plasticity and invasion. Pigment Cell Melanoma Res 25(5):573–583

    Article  PubMed  CAS  Google Scholar 

  61. Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3:362–374

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

We would like to thank Dr. Jonathan Braun for fundamental discussions regarding this research. We would also like to thank Huijun Yang for the immunostaining, Meagan Kiyohara, Ann Chan and the UCLA Clinical Microarray Core for their precious technical help. We also thank Dr. Dan Welch for providing the GFP melanoma cell line and Dr Richard Scolyer for providing human specimens of melanoma.

This work was funded by a Translational Research Fund from the Department of Pathology and Laboratory Medicine at UCLA, and by a grant from the “Société Française de Dermatologie” (French Society of Dermatology).

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA) Medical Center, Los Angeles, CA, USA

    Claire Lugassy, Madhuri Wadehra, Xinmin Li, David Akhavan, Scott W. Binder, Alistair J. Cochran & Raymond L. Barnhill

  2. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles (UCLA) Medical Center, Los Angeles, CA, USA

    Claire Lugassy, Madhuri Wadehra, Xinmin Li, Scott W. Binder, Alistair J. Cochran & Raymond L. Barnhill

  3. Orthopedic Hospital Research Center, David Geffen School of Medicine, University of California Los Angeles (UCLA) Medical Center, Los Angeles, CA, USA

    Mirko Corselli & Bruno Péault

  4. Center For Cardiovascular Science, The University of Edinburgh Queen’s Medical Research Institute, Edinburgh, Scotland, UK

    Bruno Péault

  5. Laboratory of Molecular Pathology, Ludwig Institute for Cancer Research, University of California at San Diego (UCSD), La Jolla, CA, USA

    Paul S. Mischel

  6. National Institutes of Health, Bethesda, MD, USA

    Hynda K. Kleinman

Authors
  1. Claire Lugassy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Madhuri Wadehra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinmin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mirko Corselli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Akhavan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Scott W. Binder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bruno Péault
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alistair J. Cochran
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paul S. Mischel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hynda K. Kleinman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Raymond L. Barnhill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claire Lugassy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lugassy, C., Wadehra, M., Li, X. et al. Pilot Study on “Pericytic Mimicry” and Potential Embryonic/Stem Cell Properties of Angiotropic Melanoma Cells Interacting with the Abluminal Vascular Surface. Cancer Microenvironment 6, 19–29 (2013). https://doi.org/10.1007/s12307-012-0128-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12307-012-0128-5

Keywords

Search

Navigation