Oral communication, iL40

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

TYRP1, a missing link between melanogenesis and melanoma progression ?

Melanoma prognosis is based on specific pathological features of the primary lesion mainly Breslow thickness, mitotic rate, ulceration status and extent of lymph node involvement now included in the American Joint Committee on Cancer (AJCC) melanoma staging system. Excision of the primary lesion and sentinel node surveillance are quite effective in the management of early stages of the disease. In metastatic patients, the extent of lymph node involvement is also an important prognosis indicator. Many progression markers both in tissues and serum, including circulating tumor cells, have been studied but none is being used in the daily practice. There is an urgent need for reliable molecular prognostic markers to discriminate between clinical stages and predict disease progression especially with the recent very encouraging results with the anti-mutated BRAF and anti-CTLA4 strategies. Melanosomal proteins have been a focus for many studies and many has been proposed as markers and targets for therapy. One of these, is tyrosinase related protein 1 also known as gp75 glycoprotein (Tyrp1/gp75) is quite intriguing. It is the most abundant glycoprotein within both the normal and transformed melanocyte and yet has no obvious key functions. However, several observations made over the past 30 years raise numerous questions: It shares structural homology with tyrosinase and even possess a catalytic copper-containing site but without obvious enzymatic function. By contrast, mutations in its related gene (brown locus) confers OCA3 type albinism. A part of the explanation can reside in its reported stabilizing effect on tyrosinase and an increased cell sensibility to oxidative stress in general. This may be in agreement with the reported TYRP1 gene polymorphisms associated with a higher risk for melanomas. A few in vitro and animal studies reported relationships between Tyrp1 protein expression and melanoma cell proliferation and invasion. However, our group showed a discrepancy between TYRP1 gene and protein expression, and demonstrated absence of a causal relationship between Tyrp1 protein expression and pigmentation. Furthermore, although Tyrp1 is regarded a melanoma differentiation marker, our data indicate that TYRP1 mRNA expression in metastatic tissue strongly correlates with poor survival. These data question its function in pigment synthesis and underscore our lack of knowledge of its mechanism of action. Nevertheless, in addition to previous Tyrp1-based vaccines, a clinical trial has been launched recently using a human anti-Tyrp1 antibody for melanoma immunotherapy based on positive preclinical in vitro and animal studies. This antibody may thus not target pigmented melanoma cells specifically, but could as well be used for clinically more aggressive amelanotic melanomas. A thorough understanding of Tyrp1 function is critical to correctly evaluate the outcome of such trials as well as its use as a target for therapy.

Advertisement from our sponsor: