Expression and distribution of kallikrein-related peptidases 5, 7, 8 and 10 in normal apocrine gland of canine skin / Expresión y distribución de péptidos relacionados con la calicreína 5, 7, 8 y 10 en glándula apocrina normal de piel canina

SUMMARY: Apocrine glands are sweat glands that are located in the skin of the dog. Anal sac apocrine, circunanal apocrine, and mammary glands are considered modified apocrine structures, and there are about nine possible types of neoplasms and other tumors in the apocrine glands of the dog and cat, including cysts, adenoma, carcinoma, and adenocarcinoma. Thus, it is important to provide new markers to characterize these glands to improve the histopathological diagnosis. In this article, we describe the distribution of kallikrein- related peptidases 5, 7, 8, and 10 in the normal apocrine glands of the dog's skin. These proteases have been shown to play a fundamental role in the homeostasis of the human skin barrier but have been scarcely studied in canine skin.

Las glándulas apocrinas son glándulas sudoríparas que se encuentran en la piel del perro. Las glándulas apocrinas del saco anal, apocrinas circunanales y mamarias se consideran estructuras apocrinas modificadas, y existen alrededor de nueve tipos posibles de neoplasias y otros tumores en las glándulas apocrinas del perro y el gato, incluidos quistes, adenoma, carcinoma y adenocarcinoma. Por lo tanto, es importante proporcionar nuevos marcadores para caracterizar estas glándulas para mejorar el diagnóstico histopatológico. En este artículo, describimos la distribución de las peptidasas 5, 7, 8 y 10 relacionadas con la calicreína en las glándulas apocrinas normales de la piel del perro. Se ha demostrado que estas proteasas desempeñan un papel fundamental en la homeostasis de la barrera de la piel humana, pero apenas se han estudiado en la piel canina.

Isolation, culture, and identification of ceruminous gland cells.

External auditory canal (EAC) stenosis or atresia usually requires a skin graft to repair, but due to the lack of a graft containing functional glands, postoperative complications such as infection and eczema are common. The aim of this study was to isolate and characterize seed cells for the construction of tissue engineered EAC skin containing ceruminous gland by isolating and cultivating cells of ceruminous gland. In this study, EAC skin samples were harvested from adult goats for ceruminous gland cell isolation. Cell morphology and proliferation rates, expression of CK7, CK8, CK18, and CK19 (glandular cell specific-markers), and secretion of ß-defensin-1, lysozyme, and polysaccharides were evaluated at different passages to verify the presence of ceruminous gland cells and determine whether function and proliferation potential were maintained. Ceruminous glands were successfully isolated and extracted from goat EAC skin. Furthermore, the isolated glandular cells maintained robust proliferation potential, exhibited high expression of CK7, CK8, CK18, and CK19, and vigorously secreted ß-defensin-1, lysozyme, and polysaccharides in this culture system. However, expression of glandular cell specific-markers and secretory function gradually declined with increasing passage number, indicating dedifferentiation of the subcultured ceruminous gland cells after five passages. In conclusion, ceruminous glands were successfully isolated, cultured, and expanded from goat EAC skin using the serumcontaining culture system. Importantly, the isolated glandular cells retained robust proliferation potential and maintained their phenotype and function in early passages (P1-P3), indicating the method's potential application for ceruminous gland regeneration.

An Update on the Molecular and Clinical Characteristics of Apocrine Carcinoma of the Breast.

Apocrine carcinoma of the breast is a rare malignancy. According to 2019 WHO classification, apocrine cellular features and a characteristic steroid receptor profile (Estrogen receptor (ER)-negative and androgen receptor (AR)-positive) define apocrine carcinoma. Her-2/neu protein expression is reported in ∼30-50% of apocrine carcinomas, while NGS analysis showed frequent PIK3CA/PTEN/AKT and TP53 mutations Followed by deregulation in the mitogen-activated protein kinase pathway components (mutations of KRAS, NRAS, BRAF). A recent miRNA study indicates various miRNAs (downregulated hsa-miR-145-5p and upregulated 14 miRNAs such as hsa-miR-182-5p, hsa-miR-3135b, and hsa-miR-4417) may target the commonly altered pathways in apocrine carcinomas such as ERBB2/HER2 and mitogen-activated protein kinase signaling pathway. Although AR expression is a hallmark of apocrine carcinoma, little is known regarding the efficacy/resistance to antiandrogens. Success of bicalutamide, a non-steroidal anti-androgen, was reported in a case of Her2-negative apocrine carcinoma. Two recent studies, however, described presence of anti-androgen resistance biomarkers (a splice variant ARv7 and AR/NCOA2 co-amplification) in a subset of AR+ apocrine carcinomas, cautioning the use of anti-androgens in AR+ triple-negative breast carcinomas. Apocrine carcinomas rarely show biomarkers predictive of response to immune checkpoint inhibitors (PD-L1 expression, MSI-H status, and TMB-high). Therefore, a comprehensive cancer profiling of apocrine carcinomas is necessary to identify potential therapeutic targets for a truly individualized treatment approach.

An apocrine mechanism delivers a fully immunocompetent exocrine secretion.

Apocrine secretion is a recently discovered widespread non-canonical and non-vesicular secretory mechanism whose regulation and purpose is only partly defined. Here, we demonstrate that apocrine secretion in the prepupal salivary glands (SGs) of Drosophila provides the sole source of immune-competent and defense-response proteins to the exuvial fluid that lies between the metamorphosing pupae and its pupal case. Genetic ablation of its delivery from the prepupal SGs to the exuvial fluid decreases the survival of pupae to microbial challenges, and the isolated apocrine secretion has strong antimicrobial effects in "agar-plate" tests. Thus, apocrine secretion provides an essential first line of defense against exogenously born infection and represents a highly specialized cellular mechanism for delivering components of innate immunity at the interface between an organism and its external environment.

Trop2 Expression in Extramammary Paget's Disease and Normal Skin.

Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors. Sacituzumab govitecan, an antibody-drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers. However, little is known about the role of Trop2 in EMPD. In this study, we immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues. In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands. Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (p = 0.0343). These results suggest the potential use of Trop2-targeted therapy for EMPD and improve our understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan.

Soy Isoflavone Genistein Inhibits an Axillary Osmidrosis Risk Factor ABCC11: In Vitro Screening and Fractional Approach for ABCC11-Inhibitory Activities in Plant Extracts and Dietary Flavonoids.

Axillary osmidrosis (AO) is a common chronic skin condition characterized by unpleasant body odors emanating from the armpits, and its aetiology is not fully understood. AO can seriously impair the psychosocial well-being of the affected individuals; however, no causal therapy has been established for it other than surgical treatment. Recent studies have revealed that human ATP-binding cassette transporter C11 (ABCC11) is an AO risk factor when it is expressed in the axillary apocrine glands-the sources of the offensive odors. Hence, identifying safe ways to inhibit ABCC11 may offer a breakthrough in treating AO. We herein screened for ABCC11-inhibitory activities in 34 natural products derived from plants cultivated for human consumption using an in vitro assay system to measure the ABCC11-mediated transport of radiolabeled dehydroepiandrosterone sulfate (DHEA-S-an ABCC11 substrate). The water extract of soybean (Glycine max) was found to exhibit the strongest transport inhibition. From this extract, via a fractionation approach, we successfully isolated and identified genistein, a soy isoflavone, as a novel ABCC11 inhibitor with a half-maximal inhibitory concentration value of 61.5 µM. Furthermore, we examined the effects of other dietary flavonoids on the ABCC11-mediated DHEA-S transport to uncover the effects of these phytochemicals on ABCC11 function. While further human studies are needed, our findings here about the natural compounds will help develop a non-surgical therapy for AO.

Apocrine Chromhidrosis.

Apocrine chromhidrosis is a rare diagnosis that occurs due to colored sweat being secreted from the apocrine glands, which are located in the axillae, anogenital skin, and areolae and over the skin of the trunk, face, and scalp. We present the case of a 65-year-old woman who presented with a sudden onset of pink sweating affecting mainly her axillae but also her pelvis, causing staining of clothing and bed sheets. There was nil to note on examination and histology with immunostaining demonstrated focally prominent yellow-brown lipofuscin granules in the cytoplasm of the apocrine secretory cells confirming the diagnosis. The disease can have a significant psychosocial impact, and treatment remains challenging. Our case is unique because the red and pink coloring of sweat is less common in cases of apocrine chromhidrosis, which is often in favor of darker colored sweat, and the distribution involved the inguinal canal, which is also less often seen.

A new look at transudation: the apocrine connection.

Transcellular trafficking in which various molecules are transported across the interior of a cell, is commonly classified as transcytosis. However, historically this term has been used synonymously with transudation. In both cases transcellular trafficking starts with the internalization of proteins or other compounds on the basal or basolateral side of a cell and continues by their transport across the interior to the apical pole (or vice versa) where they are subsequently released. This allows a cell to release products which are synthesized elsewhere. Here, we discuss the common features of both transcytosis and transudation, and that which differentiates them. It appears that transcytosis and transudation are identical in terms of vesicular import and endosomal sorting of cargo, but completely differ in the re-secretion process. Specialized epithelial cells re-release substantial quantities of the endocytosed material, and often also a great variety. Some recent studies indicate that this is achieved by non-canonical apocrine secretion rather than by the regular vesicular mechanism of exocytosis, and takes place only on the apical pole. This massive re-release of endocytosed proteins, and potentially other compounds via the apocrine mechanism should be considered as transudation, distinct from transcytosis.

The role of histopathologic testing on apocrine carcinoma of the breast.

BACKGROUND: Apocrine carcinoma is a rare primary breast tumor characterized by the apocrine morphology. The purpose of this article is to report a review of cases with apocrine carcinoma and draw physicians' attention to the benefits of immunphenotypic techniques in cases with suspected apocrine morphology in diagnosing this uncommon breast tumor. METHODS: In this study, authors report a case series of 15 cases with apocrine carcinoma from totally 4123 breast cancer cases. Data collected between years 2008 and 2016 from Istanbul School of Medicine department of surgery archive by analyzing surgical approach to cases and immunphenotypic features of tumors according to the date of examining in our pathology department. RESULTS: In this study, Androgen, "gross cystic disease fluid protein-15" (GCDFP-15), estrogen (ER), progesterone (PR) and Her-2 neu receptor status supported evidence of apocrine carcinoma has been reviewed. As a result, HER-2 neu, GCDFP-15, androgen receptor positivity in general are useful in the diagnosis of apocrine carcinoma. In addition of these data our study revealed that GCDFP-15 positive patients are more prone to have local recurrence and distant metastases. CONCLUSIONS: We briefly describe and discuss the molecular features and new diagnostic biomarkers for this rare mammary malignancy. The importance of comprehensive profiling is highlighted due to synergistic and potentially antagonistic molecular events in the individual patients.

Cutaneous spindle cell adenolipoma with eccrine and apocrine differentiation.

Cutaneous spindle cell adenolipoma (SCAL) is a recently described rare variant of lipoma with 11 cases reported to date. Here we report a consultation case of a 77-year-old male who presented with a nodule on the right nasolabial fold, diagnosed as apocrine fibroadenoma or sebaceous hyperplasia by an outside pathologist. The specimen revealed an ill-defined dermal tumor composed of mature adipocytes, bland spindle cells, ropey collagen, and dilated eccrine and apocrine glands and ducts in a fibromyxoid stroma. The spindle cells were positive for CD34 and negative for S100 protein and SOX10. These findings are consistent with those of cutaneous SCAL. The pathogenesis of this entity is controversial and includes a hamartomatous process, derivation from adipose tissue surrounding eccrine glands, or preexisting glands entrapment within a growing lipoma. In the present case, the glandular component is extensive and includes both eccrine and apocrine differentiation, which has not been previously described and further supports the hamartomatous nature. Awareness of this rare entity is helpful to prevent confusion with other look-alike primary and metastatic cutaneous lesions.

Detection of human epidermal growth factor receptor 2 overexpression in canine anal sac gland carcinoma.

Canine anal sac gland carcinoma (ASGC) frequently occurs in the apocrine glands of the canine anal sac and shows aggressive biological behavior. The expression of human epidermal growth factor receptor 2 (HER2) has been reported in various human and canine tumors. HER2 is a promising therapeutic target of these tumors, and HER2-targeted drugs, such as trastuzumab and lapatinib, have improved the outcome of these patients. In this study, HER2 expression in ASGC was evaluated to investigate its potential as a therapeutic target for canine ASGC. HER2 mRNA expression in surgically resected ASGC tissues was significantly higher than that in normal anal sac tissue. To evaluate the expression of HER2 protein, paraffin-embedded ASGC tissues were immunohistochemically evaluated. Strong and broad staining of HER2 was detected in ASGC tissues, while HER2 was weakly to moderately stained in normal anal sac apocrine glands and squamous epithelia. The degree of HER2 expression in ASGC tissues was scored based on its intensity and positivity (score: 0-3+). Scoring of HER2 expression revealed 6 samples (24%) scored 3+, 14 (56%) scored 2+, and 5 (20%) scored 1+, with no samples scoring 0. In all, 80% of canine ASGC tissues were positive for HER2 (scored ≥2+). Furthermore, putative HER2-overexpressed cells in ASGC were detected with trastuzumab by flow cytometry. These preliminary data may lead to further evaluation of the role of HER2 in canine ASGC as a mechanism of malignancy and as a therapeutic target for HER2-targeted therapy.

Detergent-resistant domains in Spodoptera frugiperda midgut microvillar membranes and their relation to microapocrine secretion.

The midgut from lepidopteran insects has a particular way to release proteins to the lumen, named microapocrine secretion that could be an adaptation to release secretory contents into the lumen at water absorbing regions. In this process small vesicles (microapocrine vesicles) bud from the midgut microvilli as double membrane vesicles, where the inner membrane comes from the secretion vesicle and the outer one from the microvillar membrane. The molecular machinery associated with this process may be recruited by specific midgut microvilli membrane domains. To address to this, Spodoptera frugiperda midgut microvillar membranes, prepared by magnesium treatment and free from cytoskeleton with the hyperosmotic Tris procedure, were submitted to detergent extraction and fractionated by density gradient ultracentrifugation. Detergent-resistant membrane domains (DRM) were recovered and their proteins identified by proteomics. Microapocrine vesicles were isolated by washing the luminal surface of the midgut epithelium, followed by freezing and thawing plus centrifugation to recover only membranes. Proteins from purified microvillar membranes and microapocrine vesicle membranes were identified by proteomics. Comparison of the two populations suggests that the budding of microapocrine vesicles surrounded by microvillar membrane is not a random process, because only around 50% of the microvillar membrane proteins are in the microapocrine vesicles. From the 16 proteins from DRM, 14 were enriched in the microapocrine membrane vesicles. These results suggest that on budding, the microapocrine vesicle membrane is enclosed by DRM and a surrounding area of the microvillar membrane. It is proposed that the DRMs somehow recruit the proteins composing the secretory machinery.

Columnar Cell Lesion and Apocrine Hyperplasia of the Breast: Is There a Common Origin? The Role of Prolactin-induced Protein.

Noninvasive breast lesions encompass a heterogeneous group of risk indicators and nonobligate precursors of breast cancer, such as apocrine hyperplasia (AH) and columnar cell lesions (CCLs). Given the different expression of ER and ER-regulated genes in AH and CCL, these two alterations are currently considered discrete conditions. However, whether they share early biologic changes is not clear to date. Here, we sought to define the clinicopathologic and immunohistochemical features of a prospective series of combined lesions made up by CCLs and AH forming a continuum within single terminal duct-lobular units. The study group included 19 cases, whereas 25 cases of synchronous contiguous CCLs and AH served as control group. The different components of each case were subjected to immunohistochemical analysis for ER, PR, AR, HER2, BCL2, CCND1, MUC1, and PIP. Although CCLs and AHs arising in continuity showed opposite patterns of ER expression, the PIP-positive apocrine signature was consistently present in both components. In conclusion, apocrine changes are highly recurrent in CCLs growing within foci of AH, regardless of the ER activation. Our results suggest that PIP-positive and PIP-negative CCLs are likely to represent biologically distinct conditions and that apocrine changes might occur earlier than ER activation in the natural history of breast precursor lesions.

Apocrine lesions of the breast: part 2 of a two-part review. Invasive apocrine carcinoma, the molecular apocrine signature and utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast.

Pure apocrine carcinoma of the breast is rare and has been defined by using a combination of morphologic (apocrine morphology in >90% of tumour cells) and immunohistochemical criteria (oestrogen receptor (ER) and progesterone receptor (PR) negative and androgen receptor (AR) positive). Recent advances in the molecular classification of breast tumours have uncovered a subset of breast tumours associated with high expression of androgen receptor mRNA including the so-called 'luminal androgen receptor (LAR) tumours' and 'molecular apocrine tumours' (MATs). Recognition of these tumour subsets has opened potential avenues for therapies exploiting the AR pathway in triple negative breast carcinoma (TNBC). In this second part of our two-part review, we focus on the definition of pure apocrine carcinoma, recent advances in understanding the molecular apocrine signature in breast carcinoma, its relationship to pure apocrine carcinoma defined at the level of light microscopy and immunohistochemistry (IHC) and the therapeutic implications of androgen expression in TNBC. We complete the article with a summary of the utility of IHC in stratifying apocrine lesions of the breast.

Testicular regulation of seasonal change in apocrine glands in the back skin of the brown bear (Ursus arctos).

Brown bears communicate with other individuals using marking behavior. Bipedal back rubbing has been identified as a common marking posture. Oily substances are secreted via enlarged sebaceous glands in the back skin of male bears during the breeding season. However, whether apocrine gland secretions are associated with seasonal changes remains unknown. The present study aimed to identify histological and histochemical changes in the secretory status and the glycocomposition of the apocrine glands in the back skin of male bears in response to changes in seasons and/or reproductive status. The apocrine glands of intact males during the breeding season were significantly larger and more active than those of castrated males during the breeding season and those of intact males during the non-breeding season. Lectin histochemical analyses revealed a more intense reaction to Vicia villosa agglutinin (VVA) in the cytoplasm, mainly Golgi zones of apocrine cells during the breeding season among castrated, compared with intact males. Positive staining for VVA was quite intense and weak in intact males during the non-breeding and breeding seasons, respectively. Ultrastructural analysis revealed VVA positivity in the Golgi zone, especially around secretory granules in apocrine cells. Changes in lectin binding might reflect a change in the secretory system in the apocrine cells. The present histological and histochemical findings of changes in the secretory status and glycocomposition of the apocrine glands according to the season and reproductive status suggest that these glands are important for chemical communication.

Triple Negative Apocrine Carcinomas as a Distinct Subtype of Triple Negative Breast Cancer: A Case-control Study.

BACKGROUND: Invasive triple negative apocrine carcinoma (TNAC) of the breast is a rare type of triple negative breast cancer. Several studies reported significantly distinct prognosis for TNAC when compared with most of the non-apocrine triple negative (NATN) tumors. This is a case-control study reporting onoutcomes from our long-term single-center experience. PATIENTS AND METHODS: We analyzed the clinicopathologic features of a series of 46 TNAC tumors treated in a 15-year period. Tumor characteristics and outcomes have been compared with a homogeneous control series of 43 NATN tumors treated during the same follow-up period. Local relapse-free survival (LRFS), distant metastases-free survival (DMFS), and overall survival (OS) have been evaluated. RESULTS: LRFS in the TNAC group was 85% and 78% at 5 and 10 years, respectively. LRFS in the NATN group was 90% and 79% at 5 and 10 years, respectively (hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.41-3.19; P = .80). DMFS in the TNAC group was 85% and 85% at 5 and 10 years, respectively. DMFS in the NATN group was 85% and 75% at 5 and 10 years, respectively (HR, 0.39; 95% CI, 0.14-1.08; P = .071). OS in the TNAC group was 86% and 83% at 5 and 10 years, respectively. OS in the NATN group was 86% and 63% at 5 and 10 years, respectively. OS was significantly better in the TNAC group (HR, 0.45; 95% CI, 0.20-0.99; P = .049). CONCLUSIONS: TNAC seems to represent a distinct group of triple negative breast cancer, characterized by a favorable long-term outcome when compared with NATN tumors.

A case report of a primary apocrine adenocarcinoma of the eyelid with literature review.

INTRODUCTION: Primary Apocrine adenocarcinomas (PAA) are very infrequent tumors that are often confused initially with benign lesions. Little is known about this disease and there is still much to be clarified. We present a case of PAA on the eyelid successfully treated with surgery alone and a literature review regarding what is currently described about this disease. METHODS: Noncomparative, retrospective case report of a patient with PAA on the eyelid succesfully treated with surgery alone and a literautre review. RESULTS: A 91-year-old man with a 2 months lesion on the upper left eyelid was treated with surgery alone with oncological margins of 5mm. The Hystopathology diagnosis was a PAA of the eyelid and free margins were obtained. After 12 months of follow-up, the patient does not show any signs of local recurrence or distant metastasis. A review of the literature suggests these tumors are located more frequently in the axilla (50%) and secondly in the head and neck (35%), with similar distribution in the upper (41%) and lower eyelid (45%). The most commonly used treatment is surgical excision, but radiotherapy and chemotherapy have also been used with variable results. CONCLUSIONS: PAA is a very rare and aggressive tumor. Because it is so infrequent, treatments are based on the sporadic cases encountered in the literature. As more cases are reported, more can be elucidated about the characteristics of this tumor, its behavior and best treatment choice and this may allow progress in the understanding and management of this disease.

Neural control of sweat secretion: a review.

BACKGROUND: Humans have 4 million exocrine sweat glands, which can be classified into two types: eccrine and apocrine glands. Sweat secretion, a constitutive feature, is directly involved in thermoregulation and metabolism, and is regulated by both the central nervous system (CNS) and autonomic nervous system (ANS). OBJECTIVES: To explore how sweat secretion is controlled by both the CNS and the ANS and the mechanisms behind the neural control of sweat secretion. METHODS: We conducted a literature search on PubMed for reports in English from 1 January 1950 to 31 December 2016. RESULTS AND CONCLUSIONS: Acetylcholine acts as a potent stimulator for sweat secretion, which is released by sympathetic nerves. ß-adrenoceptors are found in adipocytes as well as apocrine glands, and these receptors may mediate lipid secretion from apocrine glands for sweat secretion. The activation of ß-adrenoceptors could increase sweat secretion through opening of Ca2+ channels to elevate intracellular Ca2+ concentration. Ca2+ and cyclic adenosine monophosphate play a part in the secretion of lipids and proteins from apocrine glands for sweat secretion. The translocation of aquaporin 5 plays an important role in sweat secretion from eccrine glands. Dysfunction of the ANS, especially the sympathetic nervous system, may cause sweating disorders, such as hypohidrosis and hyperhidrosis.

Ultrastructure and immunohistochemical characterization of proteins concerned with the secretory machinery in goat ceruminous glands.

The expression of soluble N-ethyl-maleimide sensitive fusion attachment protein receptor (SNARE) proteins in apocrine glands has not been fully elucidated. In addition to performing ultrastructural observation of the ceruminous glands in goats, our study focuses on the demonstration of ß-defensins, SNARE proteins and Rab3D in these glands with the use of immunohistochemical methods. The secretory cells were equipped with two types of vesicles, Golgi apparatus and abundant rough endoplasmic reticulum (ER). Additionally, in some of them, the characteristic concentric structures composed of rough ER were observed in their circum- and infranuclear parts. The expression of phosphorylated inositol requiring enzyme 1a was also detected. These findings may indicate their ability to produce numerous secretory proteins and the maintenance of homeostasis in the glandular cells. Furthermore, ß-defensins were demonstrated as products of the ceruminous glands. The present investigation also revealed the presence of SNARE proteins and Rab3D. It is suggested that these proteins are concerned with the secretory machinery of this gland type.