Fibromodulin: Linking blood vessels and skin pigment
Links between pigmentation and angiogenesis have long been suspected but have not been formally proven. In the most recent issue of the Journal of Clinical Investigation (JCI), the link between pigmentation and angiogenesis is explored in depth. Adini et al found that implantation of fibroblast growth factor in the avascular cornea of albino C57BL6 mice led to a much more vigorous angiogenic response than in the wild type (black) C57BL6 mouse (Adini et al., 2014). To further explore the differences between these strains, differences in factors between albino and normal melanocytes were explored, and a candidate gene product, fibromodulin, was found to be present in nonpigmented melanocytes, but not in pigmented melanocytes. To definitively prove the role of fibromodulin, knockout mice for fibromodulin were crossed into the C57Bl6 albino strain, and mice that were deficient in fibromodulin were less proficient in pathologic angiogenesis than parental C57BL6 albino mice. These findings have potential relevance in the chemoprevention of melanoma. In fact, one could envision writing an RO1 grant with specific aims that dissect the potential role of fibromodulin in melanomagenesis.
While albinism predisposes to melanoma, it is by far not the most common scenario. Patients with melanocortin 1 receptor mutations (MC1R) are far more common than albinos, and they have a relatively high risk of melanoma. Melanocytes with MC1R mutations produce phaeomelanin, which differs from eumelanin in several biochemical aspects (Fargnoli et al., 2008; Wakamatsu et al., 2006). Phaeomelanin has been hypothesized to generate reactive oxygen compared to eumelanin, and it would be of interest to determine whether melanocytes deficient in MC1R produce increased fibromodulin compared with melanocytes with normal MC1R function. A second specific aim, based upon preliminary data from a comparison of MC1R mutant melanocytes with normal melanocytes, would be whether secretion of fibromodulin could be pharmacologically reversed by agents that promote pigmentation. These could be thymidine dinucleotides, or agents that activate microopthalmia and cyclic AMP (MITF) signaling, such as forskolin (Arad et al., 2008;Lin et al., 2002). Also, if fibromodulin is induced by reactive oxygen signaling, it could be inhibited by reactive oxygen inhibitors such as N-acetylcysteine or NADPH oxidase inhibitors such as imipramine blue (Cotter et al., 2007;Munson et al., 2012). Finally, the availability of genetic models of human melanoma would allow crossing a tamoxifen inducible Braf V600E/PTEN null mouse into a fibromodulin knockout background to determine whether the incidence and progression of melanoma is altered by lack of fibromodulin.
Several questions are still unanswered. Darkly pigmented individuals do not lack in angiogenesis. Indeed, they have greater susceptibility to keloids, which produce high levels of vascular endothelial growth factor (Gira et al., 2004). In the JCI study, fibromodulin was shown to alter the response to bFGF, but the effects on VEGF mediated vascularization are unknown. One could envision a differential response to fibromodulin between VEGF and bFGF, and tumors which are more bFGF-dependent, i.e., basal cell carcinoma, being more affected by fibromodulin secretion than VEGF dependent tumors (Arbiser et al., 2000). Fibromodulin is also a complex molecule, and it has been shown to cause apoptosis of fibroblasts through downregulation of NFkB (Lee and Schiemann, 2011). Thus, the interplay between pigmentation and angiogenesis is significant but complex.
Adini I, Ghosh K, Adini A, Chi ZL, Yoshimura T, Benny O, Connor KM, Rogers MS, Bazinet L, Birsner AE, Bielenberg DR, D'Amato RJ: Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment. J Clin Invest 124:425-436 (2014).
Arad S, Zattra E, Hebert J, Epstein EH, Jr., Goukassian DA, Gilchrest BA: Topical thymidine dinucleotide treatment reduces development of ultraviolet-induced basal cell carcinoma in Ptch-1+/- mice. Am J Pathol 172:1248-1255 (2008).
Arbiser JL, Byers HR, Cohen C, Arbeit J: Altered basic fibroblast growth factor expression in common epidermal neoplasms: examination with in situ hybridization and immunohistochemistry. J Am Acad Dermatol 42:973-977 (2000).
Cotter MA, Thomas J, Cassidy P, Robinette K, Jenkins N, Florell SR, Leachman S, Samlowski WE, Grossman D: N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of ultraviolet-induced melanoma in mice. Clin Cancer Res 13:5952-5958 (2007).
Fargnoli MC, Pike K, Pfeiffer RM, Tsang S, Rozenblum E, Munroe DJ, Golubeva Y, Calista D, Seidenari S, Massi D, Carli P, Bauer J, Elder DE, Bastian BC, Peris K, Landi MT: MC1R variants increase risk of melanomas harboring BRAF mutations. J Invest Dermatol 128:2485-2490 (2008).
Gira AK, Brown LF, Washington CV, Cohen C, Arbiser JL: Keloids demonstrate high-level epidermal expression of vascular endothelial growth factor. J Am Acad Dermatol 50:850-853 (2004).
Lee YH, Schiemann WP: Fibromodulin suppresses nuclear factor-kappaB activity by inducing the delayed degradation of IKBA via a JNK-dependent pathway coupled to fibroblast apoptosis. J Biol Chem 286:6414-6422 (2011).
Lin CB, Babiarz L, Liebel F, Roydon PE, Kizoulis M, Gendimenico GJ, Fisher DE, Seiberg M: Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation. J Invest Dermatol 119:1330-1340 (2002).
Munson JM, Fried L, Rowson SA, Bonner MY, Karumbaiah L, Diaz B, Courtneidge SA, Knaus UG, Brat DJ, Arbiser JL, Bellamkonda RV: Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma. Sci Transl Med 4:127ra36 (2012).
Wakamatsu K, Kavanagh R, Kadekaro AL, Terzieva S, Sturm RA, Leachman S, bdel-Malek Z, Ito S: Diversity of pigmentation in cultured human melanocytes is due to differences in the type as well as quantity of melanin. Pigment Cell Res 19:154-162 (2006).