Context.— Cutaneous metastases from a distant malignancy are a diagnostic challenge for pathologists. Secondary involvement of the skin by a metastatic process portends a much worse clinical prognosis than any primary cutaneous malignant mimickers. Immunohistochemical staining methods continue to evolve and are of paramount importance in diagnosis. Objective.— To review the clinical, histopathologic, and immunohistochemical staining patterns for commonly encountered entities and discuss potential pitfalls in diagnosis. A practical guide useful in approaching cutaneous metastases of unknown primary is outlined. Data Sources.— An extensive search and review of literature in PubMed was performed, processed, and condensed. Conclusions.— Cutaneous metastases have broad histopathologic patterns. They are nearly always dermal based, with an overall foreign appearance. They can be single papules/nodules or multiple in number, mimicking an inflammatory or infectious process. Ultimately, immunohistochemistry remains an essential diagnostic tool, and clinical correlation is paramount in the workup of these entities.
Multiple myeloma (MM) is an incurable refractory hematological malignancy arising from plasma cells in the bone marrow. Here we investigated miR-26a function in MM and tested single-wall carbon nanotube delivery of miR-26a in vitro and in vivo. miR-26a was downregulated in patient MM cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation and migration and induced apoptosis in MM cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using Stable isotope labeling by amino acids in cell culture (SILAC) medium followed by mass spectrometry analysis. In MM cells overexpressing miR-26a, CD38 protein was downregulated and subsequently confirmed to be a direct target of miR-26a. Depletion of CD38 in MM cells duplicated the MM inhibition observed with exogenous expression of miR-26a, whereas restoration of CD38 overcame the inhibition of miR-26a in MM cells. In a human MM xenograft mouse model, overexpression of miR-26a inhibited CD38 expression, provoked cell apoptosis, and inhibited cell proliferation. Daratumumab is the first CD38 antibody drug for monotherapy and combination therapy for MM patients, but eventually resistance develops. In MM cells, CD38 remained at low level during daratumumab treatment, but a high quality response is sustained. In daratumumab-resistant MM cells, CD38 expression was completely restored but failed to correlate with daratumummab-induced cell death. Therefore, a therapeutic strategy to confer selection pressure to maintain low CD38 expression in MM cells may have clinical benefit. SignificanceThese results highlight the tumor suppressor function of miR-26a via its targeting of CD38 and suggest the therapeutic potential of miR-26a in MM patients.Research.
BackgroundDysregulated CD44 expression characterizes most human cancers, including prostate cancer (PCa). PCa loses expression of CD44 standard (CD44s) that is present in benign epithelium, and overexpresses the novel splice variant isoform, CD44v7-10.MethodsUsing retroviral gene delivery to PC-3M PCa cells, we expressed luciferase-only, enforced CD44s re-expression as a fusion protein with luciferase at its C-terminus or as a protein separate from luciferase, or knocked down CD44v7-10 by RNAi. Invasion, migration, proliferation, soft agar colony formation, adhesion, Docetaxel sensitivity, and xenograft growth assays were carried out. Expression responses of merlin, a CD44 binding partner, and growth-permissive phospho-merlin, were assessed by western blot.ResultsCompared to luciferase-only PC-3M cells, all three treatments reduced invasion and migration. Growth and soft agar colony formation were reduced only by re-expression of CD44s as a separate or fusion protein but not CD44v7-10 RNAi. Hyaluronan and osteopontin binding were greatly strengthened by CD44s expression as a separate protein, but not a fusion protein. CD44v7-10 RNAi in PC-3M cells caused marked sensitization to Docetaxel; the two CD44s re-expression approaches caused minimal sensitization. In limited numbers of mouse subcutaneous xenografts, all three alterations produced only nonsignificant trends toward slower growth compared with luciferase-only controls. The expression of CD44s as a separate protein, but not a fusion protein, caused emergence of a strongly-expressed, hypophosphorylated species of phospho-merlin.ConclusionStable re-expression of CD44s reduces PCa growth and invasion in vitro, and possibly in vivo, suggesting CD44 alterations have potential as gene therapy. When the C-terminus of CD44s is fused to another protein, most phenotypic effects are lessened, particularly hyaluronan adhesion. Finally, CD44v7-10, although it was not functionally significant for growth, may be a target for chemosensitization.
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