The most widely accepted treatment for cutaneous angiosarcoma (CAS) is wide local excision and postoperative radiation to decrease the risk of recurrence. Positive surgical margins and large tumors (T2, >5 cm) are known to be associated with poor prognosis. Moreover, T2 tumors are known to be associated with positive surgical margins. According to previous reports, the majority of CAS patients in Japan had T2 tumors, whereas less than half of the patients in the studies from western countries did so. Consequently, the reported 5-year overall survival of Japanese CAS patients without distant metastasis was only 9%, lower than that for stage-IV melanoma. For patients with T2 tumors, management of subclinical metastasis should be considered when planning the initial treatment. Several attempts to control subclinical metastasis have been reported, such as using adjuvant/neoadjuvant chemotherapy in addition to conventional surgery plus radiation. Unfortunately, those attempts did not show any clinical benefit. Besides surgery, new chemotherapeutic approaches for advanced CAS have been introduced in the past couple of decades, such as paclitaxel and docetaxel. We proposed the use of chemoradiotherapy (CRT) using taxanes instead of surgery plus radiation for patients with T2 tumors without distant metastasis and showed a high response ratio with prolonged survival. However, this prolonged survival was seen only in patients who received maintenance chemotherapy after CRT, indicating that continuous chemotherapy is mandatory to control subclinical residual tumors. With the recent development of targeted drugs for cancer, many potential drugs for CAS are now available. Given that CAS expresses a high level of vascular endothelial growth factor (VEGF) receptor, drugs that target VEGF signaling pathways such as anti-VEGF monoclonal antibody and tyrosine kinase inhibitors are also promising, and several successful treatments have been reported. Besides targeted drugs, several new cytotoxic anticancer drugs such as eribulin or trabectedin have also been shown to be effective for advanced sarcoma. However, most of the clinical trials did not include a sufficient number of CAS patients. Therefore, clinical trials focusing only on CAS should be performed to evaluate the effectiveness of these new drugs.

The terminal differentiation of the epidermis is a complex physiological process. During the past few decades, medical genetics has shown that defects in the stratum corneum (SC) permeability barrier cause a myriad of pathological conditions, ranging from common dry skin to lethal ichthyoses. Contrarily, molecular phylogenetics has revealed that amniotes have acquired a specialized form of cytoprotection cornification that provides mechanical resilience to the SC. This superior biochemical property, along with desiccation tolerance, is attributable to the proper formation of the macromolecular protein-lipid complex termed cornified cell envelopes (CE). Cornification largely depends on the peculiar biochemical and biophysical properties of loricrin, which is a major CE component. Despite its quantitative significance, loricrin knockout (LKO) mice have revealed it to be dispensable for the SC permeability barrier. Nevertheless, LKO mice have brought us valuable lessons. It is also becoming evident that absent loricrin affects skin homeostasis more profoundly in many more aspects than previously expected. Through an extensive review of aggregate evidence, we discuss herein the functional significance of the thiol-rich protein loricrin from a biochemical, genetic, pathological, metabolic, or immunological aspect with some theoretical and speculative perspectives.

Loricrin is a major component of the cornified cell envelope, a highly insoluble structure composed of covalently cross-linked proteins. Although loricrin knockout mice only exhibit a mild transient phenotype at birth, they show a marked delay in the formation of an epidermal barrier in utero. We recently discovered that induction of a compensatory response to repair the defective barrier is initiated by amniotic fluid via activation of NF-E2-related factor 2 and identified Sprr2d and Sprr2h as direct transcriptional targets. Proteomic analysis suggested that other proteins were also incorporated into the loricrin knockout cell envelope, in addition to the small proline rich proteins. Here we present evidence suggesting that the late cornified envelope 1 proteins are also compensatory components as determined by their localization within the loricrin knockout cell envelope via immunoelectron microscopy. We also demonstrate that late cornified envelope 1 genes are upregulated at the transcriptional level in loricrin knockout mouse skin and confirm that late cornified envelope 1 genes are transcriptional targets of NRF2. Our present study further highlights the complexity and importance of a compensatory mechanism that evolved in terrestrial animals to ensure the formation of a functional epidermal barrier.

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