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Dermatology Research and Practice
Volume 2010 (2010), Article ID 185687, 6 pages
http://dx.doi.org/10.1155/2010/185687
Review Article

Angiogenesis and Progression in Human Melanoma

1Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari I-70124, Italy
2Department of Human Anatomy and Histology, University of Bari Medical School, Bari I-70124, Italy

Received 21 December 2009; Accepted 6 April 2010

Academic Editor: Keith Hoek

Copyright © 2010 R. Ria et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In tumor growth, angiogenesis, the process of new-formation of blood vessels from pre-existing ones, is uncontrolled and unlimited in time. The vascular phase is characterized by the new-formation of vascular channels that enhances tumor cell proliferation, local invasion and hematogenous metastasis. Human malignant melanoma is a highly metastatic tumor with poor prognosis, and high resistance to treatment. Parallel with progression, melanoma acquires a rich vascular network, whereas an increasing number of tumor cells express the laminin receptor, which enables their adhesion to the vascular wall, favouring tumor cell extravasation and metastases. Melanoma neovascularization has been correlated with poor prognosis, overall survival, ulceration and increased rate of relapse. Secretion of various angiogenic cytokines, i.e. VEGF-A, FGF-2, PGF-1 and -2, IL-8, and TGF-1 by melanoma cells promote the angiogenic switch and has been correlated to transition from the radial to the vertical growth phase, and to the metastatic phase. Moreover, melanoma cells overexpress v 3, v 5, 2 1 and 5 1 integrins and release, together with stromal cells, higher amount of metalloproteases that increasing their invasive potential and angiogenesis. Basing on these observations, different molecular targets of antiangiogenic molecules has be recognized and various antiangiogenic agents are currently in preclinical and clinical trials for melanoma.

1. Introduction

Angiogenesis, the process of new formation of blood vessels from preexisting ones, takes place in both physiological and pathological conditions, such as chronic inflammation and cancer [1, 2]. In tumor growth, angiogenesis is uncontrolled and unlimited in time and it is involved in the transition from the avascular to the vascular phase [3], the so-called angiogenic switch, in which the balance between angiogenesis inducers and inhibitors leans towards the former [4]. The vascular phase is characterized by the new formation of vascular channels that enhance tumor cell proliferation, local invasion, and hematogenous metastasis.

2. Angiogenesis in Human Melanoma

Human malignant melanoma is a highly metastatic tumor with poor prognosis and high resistance to treatment. It progresses through different steps: nevocellular nevi, dysplastic nevi (when these two entity can be identified as primary events in melanocytic neoplasia progression), in situ melanoma, radial growth phase melanoma (Breslow index 0.75 mm), vertical growth phase melanoma (index 0.75 mm), and metastatic melanoma [5]. Primary tumor grows horizontally through the epidermis; over time, a vertical growth phase component intervenes and melanoma increases its thickness and invades the dermis. Once a vertical growth phase has developed, there is a direct correlation between the tumor thickness and the number of metastases [6].

Parallel with progression, melanoma acquires a rich vascular network, whereas an increasing number of tumor cells express the laminin receptor, which enables their adhesion to the vascular wall, favouring tumor cell extravasation and metastases [79]. Melanoma neovascularization has been correlated with poor prognosis, overall survival, ulceration, and increased rate of relapse [1012].

3. The Role of Angiogenic Cytokines

Secretion of vascular endothelial growth factor-A (VEGF-A) by melanoma cells has been correlated to the transition from the radial to the vertical growth phase, and to the metastatic phase [1315]. Ribatti et al. [12] have demonstrated that increased microvascular density, strong VEGF-A tumor immunoreactivity, increased vascular diameter, and high number of vascular pillars—expression of the intussusceptive microvascular growth—are correlated to a high Breslow index ( 3.6 mm). Salven et al. [15] have demonstrated that up-regulation of VEGF-A expression in metastatic melanoma is associated with an increase in the number of tumor-infiltrating inflammatory cells expressing VEGF-A. Finally, melanotransferrin, which is angiogenic in vitro and in vivo, is overexpressed in human melanoma and correlates to the tumor VEGF-A expression and progression [16].

Fibroblast growth factor-2 (FGF-2) is overexpressed in human melanoma and may be induced by an increased release by tumor cells of matrix metalloproteinases (MMPs) which, in turn, degrade extracellular matrix inducing the release of FGF-2 stored there as an inactive form. Ribatti et al. [17] have demonstrated a significant correlation between melanoma progression, percentage of FGF-2-expressing tumor cells, and the number of mast cells which, in turn, secrete other angiogenic molecules, such as VEGF-A [15].

Another important stimulator of melanoma angiogenesis is placental growth factor (PGF). PGF-1 and -2 are expressed by melanoma cells and known to bind neuropilin-1 and -2 receptors expressed on endothelial cells [18]. In addition, PGF acts through binding to VEGF receptor-1 inducing the mobilization and recruitment of VEGFR-1+ hematopoietic precursors from bone marrow and enhancing blood vessel maturation by acting on VEGFR-1-expressing smooth muscle cells/pericytes [19]. Moreover, PGF forms heterodimers with VEGF-A and enhances melanoma angiogenesis by activating VEGFR-2 on endothelial cells [19, 20].

Interleukin-8 (IL-8) expression was found to be very little in normal epidermis and benign melanocytic lesions. However, it is dramatically increased in a majority of cutaneous melanomas. Its serum levels in patients are significantly elevated compared to healthy individuals and correlate with advanced disease stage as well as with overall survival [21]. Melanoma-derived IL-8 is able to induce endothelial cell migration, modulate vascular permeability, and enhance actin stress fiber formation. These activities resulted in enhanced angiogenesis, rapid tumor growth, and increased metastatic potential [22, 23]. Liu et al. [24] have demonstrated that transforming growth factor-1 (TGF-1) is able to enhance expression of IL-8 in human melanoma cells and promote angiogenesis in several mouse xenograft models.

4. Integrin Signaling and Extracellular Matrix Enzymes

Vacca et al. [7, 9] have demonstrated that melanoma cells express the 67-kDa laminin receptor in step with the progression from the nevocellular to the dysplastic nevi, and from the primary to the metastatic tumor. This expression enables melanoma cell adhesion to the vascular wall and together with the increased vascular network favors tumor cell extravasation and metastasis.

Overexpression of v 3, v 5, 2 1, and 5 1 integrins has been correlated with the transition from primary to metastatic melanoma [25]. In turn, integrins overexpression stimulates MMP-2 and MMP-7 in melanoma cells, increasing their invasive potential [26].

Melanoma and tumor stromal cells express several MMPs, including MMP-1, -2, -3, -7, -9, -14, -15, -16, as well as tissue inhibitors of MMPs such as TIMP-1, -2, and -3 [27]. MMPs overexpression has been correlated with increased microvascular density, Bcl-2 overexpression, and low survival rate. The most extensively studied MMPs in melanomas are MMP-2 and MMP-9. The expression and activation of both enzymes have been correlated to the invasive and metastatic phenotypes of the tumors [2731] in which they are constitutively expressed and highly associated with atypia and dedifferentiation into melanocytic lesions [28]. MMP-2 expression was highly correlated with the metastatic spread and low survival rates [27]. Moreover, functional activity of MMPs is required for tumor progression. Overexpression of MT1-MMP in melanoma cells induced activation of MMP-2 which is crucial for extracellular matrix degradation. MMP-2 and MT1-MMP+ tumor cells were often restricted to the interface between the tumor invasive part and stroma [32, 33]. Expression of MMPs is not restricted to tumor cells but is also found abundantly in stromal cells indicating a major contribution of host-derived proteases to tumor progression [34]. Also MMP-1 expression is highly associated with melanoma progression [29]. MMP-9 expression in melanoma cells was found exclusively during the horizontal growth phase but not during the vertical phase. This clearly suggests that expression of MMP-9 is an early event in melanoma progression [28].

Several studies using either cell lines or animal models have demonstrated that the balance between MMPs and their inhibitors (TIMPs) finally determines melanoma progression [3339]. Overexpression of TIMP-1, -2, and -3 significantly reduces melanoma tumor cell invasion, migration, growth and metastasis, and significantly reduces tumor neovascularization in the several tumor models studied [40].

Urokinase plasminogen activator and its receptor (uPA/uPAR) have been demonstrated to play a crucial role in several stages of melanoma progression including tumor cell migration, invasion, and metastasis. uPA secreted from melanoma cells is able to regulate endothelial cell functions including migration and the organization of endothelial cells into tube-like structures [4143].

The extracellular matrix enzymes and their inhibitors play also an important role in cancer dysregulated angiogenesis [44, 45]. These enzymes are the major degrading enzymes produced by angiogenic endothelial cells for migration trough extracellular matrix during neovessel formation [46]. Moreover, MMPs and TIMPs may act as regulators of signaling pathways through the cleavage of nonmatrix substrates, including cytokines, chemokines, and growth factors. In the last fifteen years, different extracellular matrix proteins and cleavage products have been identified. These molecules possess the ability to regulate vascular development, repair and function. Therefore, possible regulatory mechanisms in vascular biology controlled by different cleavage products of basement membrane proteins (e.g., endostatin and tumstatin, endorepellin), their activation by proteases and inhibitors, such as matrix metalloproteases (MMPs), cathepsins, tissue inhibitors of MMPs and cystatin, will be reviewed [47].

5. Antiangiogenic Therapies

As it is shown on Table 1, different molecular targets of antiangiogenic molecules can be recognized, so various antiangiogenic agents are currently in clinical trials for melanoma.

tab1
Table 1: Molecular targets of antiangiogenic drugs.

Thalidomide has been found to have antiangiogenesis and antiinflammatory properties, and accordingly it has been used as a therapeutic agent in some malignant tumors including liver, renal cell, and breast carcinomas [48]. Thalidomide inhibits vasculogenic mimicry channel and mosaic vessels formation in melanoma through the regulation of vasculogenic factors, and it can induce necrosis of tumor cells, which may be related with the NF-kappaB signaling pathway [49, 50]. Many studies are also focused on the effects of thalidomide on advanced melanoma alone [51, 52] or in combination with Interferon alpha 2 b [53, 54], temozolomide [55, 56], and dacarbazine [57] with encouraging results.

On the basis of preclinical findings indicating that continuous low dose (metronomic) chemotherapy is thought to inhibit tumor angiogenesis, [58] the evaluation of antiangiogenic potency of various chemotherapeutic drugs for metronomic chemotherapy, particularly taxol, is ongoing for its efficacy.

Semaxanib, a small molecule inhibitor of the VEGFR-2 tyrosine kinase, has shown encouraging results in patients with metastatic melanoma [59, 60] in whom it has also been evaluated in combination with thalidomide to assess the efficacy, tolerability, pharmacokinetic, and pharmacodynamic characteristics [61]. The results of this last study have demonstrated that the combination semaxanib-thalidomide is feasible and demonstrated antitumor activity in patients with metastatic melanoma who had failed prior therapy.

Another way to inhibit angiogenesis is the inhibition of matrix metalloproteinase (MMP) activity. In the early 1990, MMP inhibitors generated great enthusiasm among several research groups wishing to take them to clinical trials. Preclinical trials of MMP inhibitors were very promising, showing minimum side effects compared to other drugs available at the time. Several current inhibitors, which have been tested in preclinical and clinical trials, are broad category MMP inhibitors [6264]. Pharmacological inhibitors such as prinomastat, batimastat, and its analog marimastat, which interfere with the catalytic site of the MMPs, were the first inhibitors studied in detail. Most of the inhibitors tested in clinical trials were not very promising due to the lack of positive outcomes and the appearance of substantial drug side effects, which were not observed in preclinical studies. Therefore, most of the inhibitor clinical trials were terminated following phase 3 clinical trials [63, 64].

Good therapeutic effects have been obtained in little studies with the combination of bevacizumab (the anti-VEGF monoclonal antibody) and chemotherapy in advanced melanoma [6568]. Moreover, preclinical data strongly support the use of a combination of bevacizumab and erlotinib, a tyrosine kinase receptors inhibitor [67].

PI-88, a potent inhibitor of heparanase, demonstrates an overall survival and time to progression similar to standard chemotherapy [69].

Preclinical data suggest that the ectopic expression of alphaIIb beta3 in melanoma cells can be exploited as a novel target of antibody therapy [70].

Although most of these study have obtained encouraging results, further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.

Finally, antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing vasculogenic mimicry as an alternative circulatory system [71]. When the endothelium-dependent vessels are inhibited by the effective angiogenesis inhibitors, the hypoxia of tumor cells caused by antiangiogenesis may increase vasculogenic mimicry compensatively which can replace the job of endothelium-dependent vessels to maintain the tumor blood supply and provide a convenient route of tumor metastasis. As a result, antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing vasculogenic mimicry.

6. Concluding Remarks

Angiogenesis in melanoma is crucial for tumor progression and metastasic escape. Since this process involves a synergistic action of several classes of angiogenic molecules and signaling pathways (Figure 1), several possibilities exist for the development of antiangiogenic therapeutic strategies. Numerous angiostatic compounds are already in clinical trials, but these approaches should be further developed.

185687.fig.001
Figure 1

Acknowledgments

This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, the Ministry of Education, Universities and Research (MIUR, PRIN Projects 2007), and the Ministry of Health, Progetto Oncologia 2006, Humanitas Mirasole S.p.A., Rome, Italy.The authors would like to thank Professor C. Perillo for English editing of the manuscript.

References

  1. D. Ribatti, A. Vacca, and F. Dammacco, “VEGF and tumor progression in human melanoma,” in VEGF and Cancer, J. H. Harmey, Ed., pp. 48–53, Eurekah.com and Kluwer Academic/Plenum, 2004.
  2. D. Ribatti, A. Vacca, and F. Dammacco, “The role of the vascular phase in solid tumor growth: a historical review,” Neoplasia, vol. 1, no. 4, pp. 293–302, 1999. View at Scopus
  3. J. Folkman, “Tumor angiogenesis,” in The Molecular Basis of Cancer, J. Mwendelsohn, P. M. Howley, M. A. Israel, and L. A. Liotta, Eds., pp. 206–232, Saunders, Philadelphia, Pa, USA, 1995.
  4. D. Ribatti, B. Nico, E. Crivellato, A. M. Roccaro, and A. Vacca, “The history of the angiogenic switch concept,” Leukemia, vol. 21, no. 1, pp. 44–52, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. A. Breslow, “Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma,” Annals of Surgery, vol. 172, no. 5, pp. 902–908, 1970. View at Scopus
  6. D. D. Heasley, S. Toda, and M. C. Mihm Jr., “Pathology of malignant melanoma,” Surgical Clinics of North America, vol. 76, no. 6, pp. 1223–1255, 1996. View at Publisher · View at Google Scholar · View at Scopus
  7. A. Vacca, D. Ribatti, L. Roncali, et al., “Melanocyte tumor progression is associated with changes in angiogenesis and expression of the 67-kilodalton laminin receptor,” Cancer, vol. 72, no. 2, pp. 455–461, 1993. View at Scopus
  8. G. H. Mahabeleshwar and T. V. Byzova, “Angiogenesis in melanoma,” Seminars in Oncology, vol. 34, no. 6, pp. 555–565, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. A. Vacca, R. Ria, D. Ribatti, M. Bruno, and F. Dammacco, “Angiogenesis and tumor progression in human melanoma,” Recenti Progressi in Medicina, vol. 91, no. 11, pp. 581–587, 2000. View at Scopus
  10. A. Srivastava, P. Laidler, R. P. Davies, K. Horgan, and L. E. Hughes, “The prognostic significance of tumor vascularity in intermediate-thickness (0.76–4.0 mm thick) skin melanoma. A quantitative histologic study,” American Journal of Pathology, vol. 133, no. 2, pp. 419–423, 1988. View at Scopus
  11. A. Srivastava, L. E. Hughes, J. P. Woodcock, and P. Laidler, “Vascularity in cutaneous melanoma detected by Doppler sonography and histology: correlation with tumour behaviour,” British Journal of Cancer, vol. 59, no. 1, pp. 89–91, 1989. View at Scopus
  12. D. Ribatti, B. Nico, C. Floris, et al., “Microvascular density, vascular endothelial growth factor immunoreactivity in tumor cells, vessel diameter and intussusceptive microvascular growth in primary melanoma,” Oncology Reports, vol. 14, no. 1, pp. 81–84, 2005. View at Scopus
  13. H. Erhard, F. J. R. Rietveld, M. C. van Altena, et al., “Transition of horizontal to vertical growth phase melanoma is accompanied by induction of vascular endothelial growth factor expression and angiogenesis,” Melanoma Research, vol. 7, no. 2, pp. S19–S26, 1997. View at Scopus
  14. J. Marcoval, A. Moreno, J. Graells, et al., “Angiogenesis and malignant melanoma. Angiogenesis is related to the development of vertical (tumorigenic) growth phase,” Journal of Cutaneous Pathology, vol. 24, no. 4, pp. 212–218, 1997. View at Scopus
  15. P. Salven, P. Heikkilä, and H. Joensuu, “Enhanced expression of vascular endothelial growth factor in metastatic melanoma,” British Journal of Cancer, vol. 76, no. 7, pp. 930–934, 1997. View at Scopus
  16. R. Sala, W. A. Jefferies, B. B. Walker, et al., “The human melanoma associated protein melanotransferrin promotes endothelial cell migration and angiogenesis in vivo,” European Journal of Cell Biology, vol. 81, no. 11, pp. 599–607, 2002. View at Scopus
  17. D. Ribatti, A. Vacca, R. Ria, et al., “Neovascularisation, expression of fibroblast growth factor-2, and mast cells with tryptase activity increase simultaneously with pathological progression in human malignant melanoma,” European Journal of Cancer, vol. 39, no. 5, pp. 666–674, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. T. Odorisio, F. Cianfarani, C. M. Failla, and G. Zambruno, “The placenta growth factor in skin angiogenesis,” Journal of Dermatological Science, vol. 41, no. 1, pp. 11–19, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. S. Donnini, M. R. Machein, K. H. Plate, and H. A. Weich, “Expression and localization of placenta growth factor and P1GF receptors in human meningiomas,” Journal of Pathology, vol. 189, no. 1, pp. 66–71, 1999. View at Scopus
  20. A. Luttun, M. Autiero, M. Tjwa, and P. Carmeliet, “Genetic dissection of tumor angiogenesis: are PlGF and VEGFR-1 novel anti-cancer targets?” Biochimica et Biophysica Acta, vol. 1654, no. 1, pp. 79–94, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. M. Bar-Eli, “Role of interleukin-8 in tumor growth and metastasis of human melanoma,” Pathobiology, vol. 67, no. 1, pp. 12–18, 1999. View at Publisher · View at Google Scholar · View at Scopus
  22. D. A. Mahler, S. Huang, M. Tabrizi, and G. M. Bell, “Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study,” Chest, vol. 126, no. 3, pp. 926–934, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. V. O. Melnikova and M. Bar-Eli, “Bioimmunotherapy for melanoma using fully human antibodies targeting MCAM/MUC18 and IL-8,” Pigment Cell Research, vol. 19, no. 5, pp. 395–405, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. G. Liu, F. Zhang, J. Lee, and Z. Dong, “Selective induction of interleukin-8 expression in metastatic melanoma cells by transforming growth factor-β1,” Cytokine, vol. 31, no. 3, pp. 241–249, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. A. K. Bosserhoff, “Novel biomarkers in malignant melanoma,” Clinica Chimica Acta, vol. 367, no. 1-2, pp. 28–35, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. S. Kuphal, R. Bauer, and A.-K. Bosserhoff, “Integrin signaling in malignant melanoma,” Cancer and Metastasis Reviews, vol. 24, no. 2, pp. 195–222, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. U. B. Hofmann, J. R. Westphal, G. N. P. Van Muijen, and D. J. Ruiter, “Matrix metalloproteinases in human melanoma,” Journal of Investigative Dermatology, vol. 115, no. 3, pp. 337–344, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. E. Kerkela and U. Saarialho-Kere, “Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer,” Experimental Dermatology, vol. 12, no. 2, pp. 109–125, 2003. View at Publisher · View at Google Scholar · View at Scopus
  29. J. Nikkola, P. Vihinen, M.-S. Vuoristo, P. Kellokumpu-Lehtinen, V.-M. Kahari, and S. Pyrhönen, “High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma,” Clinical Cancer Research, vol. 11, no. 14, pp. 5158–5166, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. J. Cotignola, B. Reva, N. Mitra, et al., “Matrix metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma,” BMC Medical Genetics, vol. 8, article 10, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. E.-M. Schnaeker, R. Ossig, T. Ludwig, et al., “Microtubule-dependent matrix metalloproteinase-2/matrix metalloproteinase-9 exocytosis: prerequisite in human melanoma cell invasion,” Cancer Research, vol. 64, no. 24, pp. 8924–8931, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. M. Durko, R. Navab, H. R. Shibata, and P. Brodt, “Suppression of basement membrane type IV collagen degradation and cell invasion in human melanoma cells expressing an antisense RNA for MMP-1,” Biochimica et Biophysica Acta, vol. 1356, no. 3, pp. 271–280, 1997. View at Publisher · View at Google Scholar · View at Scopus
  33. U. B. Hofmann, J. R. Westphal, A. J. W. Zendman, J. C. Becker, D. J. Ruiter, and G. N. P. Van Muijen, “Expression and activation of matrix metalloproteinase-2 (MMP-2) and its co-localization with membrane-type I matrix metalloproteinase (MTI-MMP) correlate with melanoma progression,” Journal of Pathology, vol. 191, no. 3, pp. 245–256, 2000. View at Scopus
  34. S. Wojtowicz-Praga, J. Torri, M. Johnson, et al., “Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer,” Journal of Clinical Oncology, vol. 16, no. 6, pp. 2150–2156, 1998. View at Scopus
  35. M. A. Rudek, W. D. Figg, V. Dyer, et al., “Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer,” Journal of Clinical Oncology, vol. 19, no. 2, pp. 584–592, 2001. View at Scopus
  36. X. Jin, M. Yagi, N. Akiyama, et al., “Matriptase activates stromelysin (MMP-3) and promotes tumor growth and angiogenesis,” Cancer Science, vol. 97, no. 12, pp. 1327–1334, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. S. Wojtowicz-Praga, J. Low, J. Marshall, et al., “Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer,” Investigational New Drugs, vol. 14, no. 2, pp. 193–202, 1996. View at Scopus
  38. B. Bodey, B. Bodey Jr., A. M. Gröger, S. E. Siegel, and H. E. Kaiser, “Invasion and metastasis: the expression and significance of matrix metalloproteinases in carcinomas of the lung,” In Vivo, vol. 15, no. 2, pp. 175–180, 2001. View at Scopus
  39. K. Airola, T. Karonen, M. Vaalamo, et al., “Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas,” British Journal of Cancer, vol. 80, no. 5-6, pp. 733–743, 1999. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. B. Anand-Apte, L. Bao, R. Smith, et al., “A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth,” Biochemistry and Cell Biology, vol. 74, no. 6, pp. 853–862, 1996. View at Scopus
  41. B. M. Mueller, “Different roles for plasminogen activators and metalloproteinases in melanoma metastasis,” Current Topics in Microbiology and Immunology, vol. 213, pp. 65–80, 1996. View at Scopus
  42. C. Delbaldo, I. Masouye, J.-H. Saurat, J.-D. Vassalli, and A.-P. Sappino, “Plasminogen activation in melanocytic neoplasia,” Cancer Research, vol. 54, no. 16, pp. 4547–4552, 1994. View at Scopus
  43. V. J. Hearing, L. W. Law, A. Corti, E. Appella, and F. Blasi, “Modulation of metastatic potential by cell surface urokinase of murine melanoma cells,” Cancer Research, vol. 48, no. 5, pp. 1270–1278, 1988. View at Scopus
  44. R. Roy, J. Yang, and M. A. Moses, “Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer,” Journal of Clinical Oncology, vol. 27, no. 31, pp. 5287–5297, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. S. C. Huang, B. C. Sheu, W. C. Chang, C. Y. Cheng, P. H. Wang, and S. Lin, “Extracellular matrix proteases—cytokine regulation role in cancer and pregnancy,” Frontiers in Bioscience, vol. 14, pp. 1571–1588, 2009. View at Scopus
  46. A. Vacca, D. Ribatti, M. Presta, et al., “Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma,” Blood, vol. 93, no. 9, pp. 3064–3073, 1999. View at Scopus
  47. F. Suhr, K. Brixius, and W. Bloch, “Angiogenic and vascular modulation by extracellular matrix cleavage products,” Current Pharmaceutical Design, vol. 15, no. 4, pp. 389–410, 2009. View at Scopus
  48. S. Singhal and J. Mehta, “Thalidomide in cancer,” Biomedicine and Pharmacotherapy, vol. 56, no. 1, pp. 4–12, 2002. View at Publisher · View at Google Scholar · View at Scopus
  49. S. Zhang, M. Li, Y. Gu, et al., “Thalidomide influences growth and vasculogenic mimicry channel formation in melanoma,” Journal of Experimental and Clinical Cancer Research, vol. 27, no. 1, article 60, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. L. Lu, F. Payvandi, L. Wu, et al., “The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions,” Microvascular Research, vol. 77, no. 2, pp. 78–86, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. L. W. Vestermark, S. Larsen, B. Lindeløv, and L. Bastholt, “A phase II study of thalidomide in patients with brain metastases from malignant melanoma,” Acta Oncologica, vol. 47, no. 8, pp. 1526–1530, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. J. Lutzky, R. Weber, Y. Nunez, et al., “A phase 1 study of granulocyte macrophage colony-stimulating factor (sargramostim) and escalating doses of thalidomide in patients with high-risk malignant melanoma,” Journal of Immunotherapy, vol. 32, no. 1, pp. 79–85, 2009.
  53. L. F. Hutchins, J. Moon, J. I. Clark, et al., “Evaluation of interferon alpha-2B and thalidomide in patients with disseminated malignant melanoma, phase 2, SWOG 0026,” Cancer, vol. 110, no. 10, pp. 2269–2275, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. U. N. Vaishampayan, L. K. Heilbrun, C. Marsack, D. W. Smith, and L. E. Flaherty, “Phase II trial of pegylated interferon and thalidomide in malignant metastatic melanoma,” Anti-Cancer Drugs, vol. 18, no. 10, pp. 1221–1226, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. I. Quirt, S. Verma, T. Petrella, K. Bak, and M. Charette, “Temozolomide for the treatment of metastatic melanoma: a systematic review,” Oncologist, vol. 12, no. 9, pp. 1114–1123, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. M. B. Atkins, J. A. Sosman, S. Agarwala, et al., “Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II cytokine working group study,” Cancer, vol. 113, no. 8, pp. 2139–2145, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. P. A. Ott, J. L. Chang, R. Oratz, et al., “Phase II trial of dacarbazine and thalidomide for the treatment of metastatic melanoma,” Chemotherapy, vol. 55, no. 4, pp. 221–227, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. J. Drevs, J. Fakler, S. Eisele, et al., “Antiangiogenic potency of various chemotherapeutic drugs for metronomic chemotherapy,” Anticancer Research, vol. 24, no. 3A, pp. 1759–1763, 2004. View at Scopus
  59. B. C. Kuenen, J. Tabernero, J. Baselga, et al., “Efficacy and toxicity of the angiogenesis inhibitor SU5416 as a single agent in patients with advanced renal cell carcinoma, melanoma, and soft tissue sarcoma,” Clinical Cancer Research, vol. 9, no. 5, pp. 1648–1655, 2003. View at Scopus
  60. A. C. Peterson, S. Swiger, W. M. Stadler, M. Medved, G. Karczmar, and T. F. Gajewski, “Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma,” Clinical Cancer Research, vol. 10, no. 12, part 1, pp. 4048–4054, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. M. M. Mita, E. K. Rowinsky, L. Forero, et al., “A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma,” Cancer Chemotherapy and Pharmacology, vol. 59, no. 2, pp. 165–174, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. I. Quirt, A. Bodurtha, R. Lohmann, et al., “Phase II study of marimastat (BB-2516) in malignant melanoma: a clinical and tumor biopsy study of the National Cancer Institute of Canada Clinical Trials Group,” Investigational New Drugs, vol. 20, no. 4, pp. 431–437, 2002. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Pavlaki and S. Zucker, “Matrix metalloproteinase inhibitors (MMPIs): the beginning of phase I or the termination of phase III clinical trials,” Cancer and Metastasis Reviews, vol. 22, no. 2-3, pp. 177–203, 2003. View at Publisher · View at Google Scholar · View at Scopus
  64. L. M. Coussens, B. Fingleton, and L. M. Matrisian, “Matrix metalloproteinase inhibitors and cancer: trials and tribulations,” Science, vol. 295, no. 5564, pp. 2387–2392, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. K. A. Varker, J. E. Biber, C. Kefauver, et al., “A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma,” Annals of Surgical Oncology, vol. 14, no. 8, pp. 2367–2376, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. D. G. Perez, V. J. Suman, T. R. Fitch, et al., “Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A,” Cancer, vol. 115, no. 1, pp. 119–127, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. L. M. Vásquez, S. Somani, F. Altomare, and E. R. Simpson, “Intracameral bevacizumab in the treatment of neovascular glaucoma and exudative retinal detachment after brachytherapy in choroidal melanoma,” Canadian Journal of Ophthalmology, vol. 44, no. 1, pp. 106–107, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. N. Schicher, V. Paulitschke, A. Swoboda, et al., “Erlotinib and bevacizumab have synergistic activity against melanoma,” Clinical Cancer Research, vol. 15, no. 10, pp. 3495–3502, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. M. Basche, D. L. Gustafson, S. N. Holden, et al., “A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors,” Clinical Cancer Research, vol. 12, no. 18, pp. 5471–5480, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. F. Mitjans, T. Meyer, C. Fittschen, et al., “In vivo therapy of malignant melanoma by means of antagonists of αv integrins,” International Journal of Cancer, vol. 87, no. 5, pp. 716–723, 2000. View at Scopus
  71. B. Qu, L. Guo, J. Ma, and Y. Lv, “Antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing an alternative circulatory system,” Medical Hypotheses, vol. 74, no. 2, pp. 360–361, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus