We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2–driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from β-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of β-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/β-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2–centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.

No abstract

No abstract

Objective: Dermoscopic features of vulvar lichen sclerosus (VLS) were investigated in order to determine both vascular and non-vascular features of this disease. Materials and Methods: Dermoscopic images of 35 patients affected with histopathologically confirmed VLS were evaluated for the presence of predefined morphological criteria. Results: On dermoscopy, VLS lesions exhibited very sparse vessels, mainly linear, without a specific arrangement. Dotted vessels were observed mostly in the early stage of the disease. Patchy, structureless areas, whitish to white-yellowish to pink-whitish in colour over a diffuse whitish background, were a distinctive and constant dermoscopic feature. Grey-blue dots, usually with a characteristic peppered arrangement, corresponding to dermal melanophages, were also frequently seen. Comedo-like openings and scales were observed, as well as peculiar structures like ice slivers, not identified by histological examination. Conclusion: Our findings show that VLS exhibits characteristic dermoscopic patterns that can aid in its clinical diagnosis.

Retroperitoneal fibrosis is a rare disease of uncertain pathogenesis. However, its possible association with several immunopathologic conditions, the possibility of systemic involvement by the fibrous process, the presence of various autoantibodies, and the frequent response to immunosuppressive treatment all support an autoimmune pathogenesis. Riedel's thyroiditis is a rare disease the pathogenesis of which is also thought to be immune-mediated based on its optimal response to steroids; Riedel's thyroiditis is also frequently reported in association with retroperitoneal fibrosis. We describe here two cases of autoimmune thyroid disease associated with retroperitoneal fibrosis, the first with features of primary myxedema, the second of primary thyrotoxicosis. Histology of retroperitoneal fibrosis is documented and it is compatible with an immunopathologic condition. Thus, these two cases add further support to the hypothesis of an autoimmune pathogenesis of retroperitoneal fibrosis and indicate the importance of carefully monitoring for the development of other autoimmune disorders, i.e., of the thyroid gland, in patients with retroperitoneal fibrosis.