Tumor necrosis factor receptor superfamily member TROY is a novel melanoma biomarker and potential therapeutic target

Abstract

Incidence of melanoma continues to rise, and a better understanding of its genetics will be critical to improve diagnosis and develop new treatments. Here, we search for novel melanoma-specific genes that may serve as biomarkers and therapeutic targets by using an in vitro genetic screen. One identified cDNA encoded TROY, a member of the tumor necrosis factor receptor superfamily (TNFRSF). TROY is widely expressed during embryogenesis, but in adults expression is restricted to hair follicles and brain. However, TROY had never been associated with melanoma, and it was selected for further study. First we show that expression in melanoma is specific by semiquantitative RT-PCR analysis of a large panel of established tumor cell lines. Next, specificity of expression was evaluated by immunohistochemistry analysis of primary cell cultures and patient tissues. TROY is expressed in 2/2 primary melanoma cells and 45/45 melanoma tissue samples (p < 0.0001). With the exception of sebaceous glands, TROY is not expressed in normal skin biopsies (p < 0.0001) or primary skin cell cultures that contain keratinocytes and epidermal melanocytes, nor is it expressed in other skin tumor cells (p < 0.0001). Finally, we show that TROY regulates melanoma growth, because replication of melanoma cells with reduced TROY levels through treatment with short-interfering RNA was significantly decreased relative to control cells (p < 0.004). In summary, TROY is the first TNFRSF member that is a biomarker for melanoma. TROY also presents a potentially novel cell surface signaling target for inhibitors, cell and/or antibody-based immunotherapies. ' 2006 Wiley-Liss, Inc.

TROY (TNFRSF19) Promotes Glioblastoma Survival Signaling and Therapeutic Resistance

“…The tightly regulated expression of TROY suggests that alterations in TROY expression may have undesirable effects on cell proliferation and migration. This suggestion is supported by the demonstration that TROY is highly expressed in primary and metastatic melanoma cells but not in normal melanocytes (35). A recent study demonstrated that TROY expression is significantly upregulated in tumor infiltrating microglia in GBM and is involved in the regulation of their migration (36).…”

Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway

“…Moreover, the combination of PPF and TMZ or radiation resulted in a significant decrease in survival compared to single-agent therapy alone, suggesting synergism between pharmacological inhibition of TROY and treatment with cytotoxic agents. TROY has also been implicated in the pathogenesis of other tumors, which suggests inhibition of TROY may be a therapy in other malignancies [12,11]. Together, these results suggest that PPF may be a potential adjuvant medication that will increase tumor vulnerability and garner improved therapeutic response in patients.…”

“…TROY is expressed in multiple cell lineages during embryogenesis, but its expression is restricted to the hair follicles and brain postnatally [7–9]. TROY is a susceptibility factor in nasopharyngeal carcinoma and metastatic lung cancer and its expression has been linked to the pathogenesis of multiple human malignancies [10–12]. In GBM, TROY overexpression activates Rac1 signaling in a Pyk2-dependent manner to drive migration and invasion [13].…”

TROY is a promising prognostic biomarker in patients with colorectal cancer

“…Recently, TROY was reported to be a β-catenin target gene and to form a complex with LGR5 in cellular membranes (13). Although overexpression of TROY is observed in CRC cell lines (14)(15)(16)(17), its clinical significance for CRC is poorly understood. Because TROY might be a possible prognostic biomarker of CRC, we performed this study to investigate the clinical significance of TROY in patients with CRC and compared its clinical usefulness to that of LGR5.…”