Fibromodulin: Linking blood vessels and skin pigment

by Guest Blogger Jack L. Arbiser, MD, PhD, Emory University School of Medicine

 

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.

 

 

References

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).

Alopecia Areata Advancement Takes a Village

by Lowell A. Goldsmith, MD

Advances in understanding alopecia areata (AA) and developing new treatments will “take a village”. The inhabitants of the village, including patients with AA, met in Bethesda Maryland in November 2012. A synopsis of their deliberations and plans is available in the JID Symposium Proceedings of December 2013. The 79-page symposium encapsulates their diversity and their analytical and scientific approaches. In  the contemporary electronic era, the proceedings of a symposium in the old-fashioned print format is still useful and powerful, exposing the reader to topics that might be glossed over with  purposed electronic searching. Print also allows reflection and reiteration, which pixels tend to inhibit. This  reflection is especially important in a complex disease like AA where genes count, the immune system counts, the neuroendocrine system probably plays a role, and where therapy is still elusive. In the village reside the best and brightest clinicians and investigators concerned with this disease.  The pioneering work of the National Alopecia Areata Foundation (NAAF) in developing and supporting the Alopecia Areata Registry, Biobank and Clinical Trials Network (Registry) continues to yield valuable data and allowed rapid gene-wide mapping studies in this disease.  (The Registry was developed and supported for 12 years by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), under award number HHSN268200682279C and is now managed and supported totally by NAAF.)

The village is now focusing on the task of developing approaches to performing critically planned, executed, and interpretable clinical trials as well as the rapid identification of new and safe drugs for treating patients with AA. Innovative animal models will aid these efforts. The village is helped in its efforts by industry, government, and private donations. There is the right mix people and questions, and when more answers are forthcoming there will be dancing and singing as the entire village celebrates with the patients, who are most keen on the outcomes  of these studies.

 

Image credit:  Cover Image from National Alopecia Areata Foundation Symposium Proceedings entitled “From Basepairs to Bedside:  Innovations in the Immunology & Clinical Science of Alopecia Areata”.

 

 

Free Indoor Tanning: Easier Access to Cancer

By Guest Blogger Liza Engstrom, Masters of Public Health student in the Health Behavior program at the University of North Carolina at Chapel Hill (liza.engstrom11@gmail.com)

 

Imagine a gym or fitness center that offers free cigarettes to its patrons. The lobby has a basket positioned on a table in the entryway full of cigarette packs and lighters, with a sign that reads “Members Smoke Free!” Now imagine gym-goers who see that sign and think: “Wow, now I can take up the habit of smoking without the added cost of buying cigarettes. And if a fitness center is offering them as a free service, they must be good for my health!”

 

Does this sound absurd? With all the existing research on the link between cigarettes and cancer, it seems very unlikely that a gym would promote tobacco smoking. But this is the case for another dangerous and addictive product. Instead of free cigarettes, many gyms now offer free indoor tanning.

 

The International Agency for Research on Cancer lists indoor suntanning under the highest risk category for cancer, deemed “carcinogenic to humans,” placing sunbeds in the same category as asbestos, arsenic, and tobacco products — and higher than well-regulated substances like lead! Yet businesses install tanning devices as if it were no different than adding a pool, sauna, or tennis court.

 

Gyms are not the only businesses that offer tanning as a free service. Apartment owners, especially those that cater largely to university students, now offer sunbeds to their residents. In the  Research Triangle area of North Carolina, more than 10 gyms and apartments offer free tanning as an amenity.

 

In targeting college students, these businesses are putting at risk those most vulnerable to tanning’s cancer-causing effects. Melanoma is the most common form of cancer for young adults ages 25-29 and the second most common for individuals aged 15-29. What’s more, research shows that use of tanning beds before the age of 35 increases one’s risk for melanoma by 87%.

 

As the recent JID article “Comprehensive Evaluation of Indoor Tanning Regulations: A 50-State Analysis, 2012”  shows, many states, including North Carolina, are in the process of issuing a ban on indoor tanning for children under 18 . But this will do nothing to protect young college students who are equally susceptible.

 

Let’s sever the link between tanning and health by disallowing fitness centers to position tanning beds alongside weights and treadmills. Indoor tanning should not be offered as a free service anywhere.