Differential expression of phospho‐S6 in hair follicle tumors: Evidence of mammalian target of rapamycin pathway activation

Abstract

Background: The role of the mammalian target of rapamycin (mTOR) in hair follicle tumorigenesis is unclear. mTOR controls cell growth and can be activated through ribosomal S6 kinase.Herein, we sought to evaluate the expression of phospho-S6 in six different benign and malignant follicular tumor types.Methods: 76 cases were selected (17 fibrofolliculomas, 20 trichoepitheliomas, 10 tricholemmomas, 19 pilomatricomas, 1 malignant proliferating tricholemmal tumor, 8 tricholemmal carcinomas, and 1 trichoblastic carcinoma) and collected over 16 years. Immunohistochemistry with monoclonal antibody for phospho-S6 was performed and analyzed semi-quantitatively; statistical analysis using the χ 2 test was performed, with P < 0.05 considered significant. Results: All malignant neoplasms in our series (8/8 [100%] cases of tricholemmal carcinoma, 1/1 [100%] trichoblastic carcinoma, and 1/1 [100%] malignant proliferating tricholemmal tumor)showed a strong and diffuse pattern of staining for phospho-S6 involving 70% to 90% of tumor cells. By contrast, a minority of benign tumors were positive for phospho-S6 and most stained in a patchy pattern including 12/17 (71%) fibrofolliculomas, 9/20 (45%) trichoepitheliomas and 1/10 (10%) tricholemmomas, involving 30% to 50%, 5% to 20%, and 40% to 50% of tumor cells, respectively. Most pilomatricomas (17/19 [89%]) exhibited a stronger, but distinctive staining pattern, staining mostly the basaloid cells with a multifocal distribution, involving 70% to 90% of tumor cells.Conclusions: Phospho-S6 is differentially expressed among benign and malignant hair follicle tumors (P = 0.0044). While malignant tumors show diffuse expression, only a small subset of benign neoplasms were positive, primarily in a patchy distribution. K E Y W O R D Shair follicle tumors, mTOR pathway, phospho-S6

Primary TSC2-/meth Cells Induce Follicular Neogenesis in an Innovative TSC Mouse Model

“…In mice injected with TSC2 -/meth cells, high S6 phosphorylation was observed in the altered areas, including thickened skin near hair bulbs and alongside mature hair. This result is consistent with the hypothesis that mTOR might drive hair follicle tumorigenesis [ 17 ]. Moreover, the phosphorylation of Erk that, together with S6 activation, might be considered a functional marker of TSC cells [ 18 ], was high in the skin of mice that received tuberin-null cells.…”

“…Phospho-S6- and phospho-Erk-positive cells in skin sections were also decreased. It was demonstrated that mTOR hyperactivation is involved in malignant hair follicle tumorigenesis [ 17 ]; so, in our model, it is possible that the transcriptional reactivation of TSC2 impairs the capability of TSC2 -/meth cells that preferentially localize in the hair bulbs to induce hair follicle formation. TSC2 -/meth cells demonstrated an intrinsic metastatic capability.…”

Identification and Molecular Analysis of m6A-circRNAs from Cashmere Goat Reveal Their Integrated Regulatory Network and Putative Functions in Secondary Hair Follicle during Anagen Stage

“…Interestingly, we noted that several enriched signaling pathways are implicated in physiological processes of hair follicles, including TGF-beta, Axon guidance, Ribosome, and Stem cell pluripotency regulatory pathways (Figure 6). For example, in previous investigations, it was recorded that the TGF-beta and mTOR signals can contribute to the activation of hair follicle stem cells by counteracting BMP-mediated suppression [44,45], whereas, the mTOR signals can be activated through ribosome S6 kinase [46]. Also, the axon guidance signals play roles in promoting the morphogenesis of hair follicles via driving the rearrangement of localized cells [47].…”