Tenascin-C promotes melanoma progression by maintaining the ABCB5-positive side population

Abstract

Tenascin-C (TNC) is highly expressed in melanoma; however, little is known about its functions. Recent studies indicate that TNC plays a role within the stem cell niche. We hypothesized that TNC creates a specific environment for melanoma cells to exhibit a stem cell-like phenotype, driving tumor growth and evading conventional therapies. TNC expression was strongly up-regulated in melanoma cells grown as 3D spheres (enriched for stem-like cells) when compared to adherent cells. Down-modulation of TNC by shRNA-lentiviruses significantly decreased the growth of melanoma spheres. The incidence of pulmonary metastases after intravenous injection of TNC knockdown cells was significantly lower in NOD/SCID IL2Rγnull mice compared to control cells. Melanoma spheres contain and increased number of side population (SP) cells, which exhibited stem cell characteristics and the potential for drug resistance due to their high efflux capacity. Knockdown of TNC dramatically decreased the SP fraction in melanoma spheres and lowered their resistance to doxorubicin treatment, likely due to the down-regulation of multiple ABC transporters, including ABCB5. These data suggest that TNC plays a critical role in melanoma progression by mediating protective signals in the therapy-resistant population of melanoma.

Melanoma stem cells: not rare, but well done

“…76 The existence of a stem cell-like population in melanoma was additionally fortified by a recent study of the effect of the ECM glycoprotein tenascin-C on melanoma progression; these data demonstrated that tenascin-C in the microenvironment encouraged manifestation of a stem cell-like phenotype in melanoma cells that included the expression of ABCB5. 77 Most recently, melanoma cells that expressed the receptor activator of NF-kB (RANK) demonstrated enhanced tumorigenicity compared with RANK-negative melanoma cells in IL-2Rg À/À NOD/SCID mice. 78 Moreover, RANK was coexpressed with ABCB5 and CD133 on melanoma cells, and preferentially expressed by peripheral circulating melanoma cells, primary melanomas, and metastases from stage IV melanomas compared with stage I melanoma patients.…”

Oct-4+/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells

“…mRNA was extracted from human NB cell lines HTLA-230 and GI-LI-N and human melanoma cell line MZ2-MEL [77] as positive control [51] using RNeasy Mini Kit from Qiagen (Qiagen GmbH, Hilden, Germany) and subjected to RT-PCR. Briefly, 1 µg of RNA was reverse transcribed using the RevertAid TM First Strand cDNA Synthesis kit (Fermentas Inc., Burlington, ON, Canada) following the instructions of the manufacturer.…”

“…Tumor-derived TNC promotes or enhances the process of neovascularization in different tumor models [23][24][25][26][27][28]51].…”

Microenvironment and tumor progression of melanoma: New therapeutic prospectives

“…In fact, studies undertaken on melanoma cellular models have shown that TNC expression was strongly up-regulated in melanoma cell growth-as 3D spheres enriched for stem-like cells when compared to in adherent cells (Fukunaga-Kalabis et al, 2010). As for other molecules present in the tumor microenvironment, it has been possible to identify TNC in the Figure 2.…”