Cornelia Amalinei

Ovarian cancer: insights into genetics and pathogeny.

Starting from the information on ovarian cancer provided by the mainstream publications, we construct a review focusing on the following issues: (i) the genetic profile, (ii) the role of the epithelial-mesenchymal transition in the acquirement of malignant features, (iii) the controversial hypothesis regarding the origin, and (iv) the involvement of the immune system in the tumoral microenvironment. Advances in the decipherment at the genetic level in the pathogenic mechanisms progressively lead to the idea of a genetic signature for the ovarian cancer. Moreover, the complementary approaches oriented towards the decryption of the intrinsic structure of the expressed molecules and, implicitly, the development of proteomics open new perspectives for an early diagnosis and an appropriate treatment. The research on the epithelial-mesenchymal transition (mainly those exploring the signaling pathways responsible for the switch between the loss of the epithelial characteristics and the gain of a mesenchymal cell phenotype, with results in the amplification of differentiation, motility and tumoral invasion) allow a deeper understanding of the complex pathogenic mechanism which governs ovarian carcinogenesis. The classic conception of ovarian cancer pathogeny, based on the role of the ovarian surface epithelium, is currently reconsidered, and a novel hypothesis is formulated, which supports direct involvement of the Fallopian tubes for the serous type. Although recent research suggests the implication of immune/inflammatory cells by specific mechanisms in ovarian cancer pathogenesis, there is yet reliable evidence concerning their modality of direct action and/or modulation of tumoral growth. Thus, ovarian carcinogenesis remains a research challenge, due to still numerous unknown factors involved in the malignant transformation sequences, originating from the genetic-molecular alterations and reflected by cellular and tissue expression patterns.

Nonclassical major histocompatibility complex I–like Fc neonatal receptor (FcRn) expression in neonatal human tissues

The neonatal Fc receptor (FcRn) was demonstrated to play a role both in the recycling and thus the protection of immunoglobulin G (IgG) from catabolism and in the maternal-fetal transfer of IgG. The expression of this particular receptor was evidenced in a variety of cell types, but the endothelial cell was considered the main cell able to perform both recycling and IgG catabolism. Based on preliminary data obtained in adult human mammary glands and skin, this study focused on a number of neonatal human tissues, targeting FcRn expression mainly in epithelial versus endothelial cells. Our results demonstrate that in most of the investigated tissues, the neonatal Fc receptor is not detectable in the endothelial cells lining the capillaries, whereas most epithelial cells are positive. We could also observe the receptors expression in most macrophages, smooth muscle cells, and neurons. Taken together, these data suggest that the main sites of IgG catabolism might in fact be other than endothelial cells in human neonates.

Immunohistochemical analysis of steroid receptors, proliferation markers, apoptosis related molecules, and gelatinases in non-neoplastic and neoplastic endometrium

Endometrioid endometrial carcinoma developed from endometrial hyperplasia is associated with anomalies of proliferation, apoptosis, and matrix metalloproteinase (MMP) expression. Our study was designed to investigate steroid receptor (ER, PR) expression and its correlation with proliferative activity (PCNA), apoptosis (Fas, FasL, Bcl-2, Bax, and p53), gelatinases (MMP-2 and MMP-9) and their tissue specific inhibitor (TIMP-1 and TIMP-2) immunoexpression in endometrial carcinogenesis. A total of 38 cases were investigated, 10 non-neoplastic, 11 hyperplastic, and 17 carcinomatous endometria. Immunolabeling showed a higher expression of steroid receptors in hyperplasia and carcinoma than in non-neoplastic endometria and an ER/PR imbalance in carcinoma. The epithelial component of endometrial carcinomas had the highest proliferative index. Bcl-2 had a stronger expression in hyperplasia and carcinoma compared to non-neoplastic endometria and stromal tissue. The Bcl-2/Bax ratio was lower in endometrial carcinoma. Fas and FasL expression was stronger in hyperplasia and furthermore in carcinoma. p53 expression was progressively stronger along the sequence non-neoplastic endometrial to hyperplasia-carcinoma. Both types of investigated MMPs showed an increased expression in neoplastic endometria reaching a maximum level in carcinomas. MMP-9 immunostaining could be correlated to myometrial invasion. TIMP-1 decreased and TIMP-2 increased in expression from non-neoplastic endometria to hyperplastic and carcinomatous endometrial, respectively. Our study demonstrates that coordinated anomalies of steroid receptors, apoptosis and invasiveness factors are already present in hyperplasia as cumulative steps along the way to malignant transformation and that a complex MMP-2, MMP-9, TIMP-2/TIMP-1 imbalance seems to be responsible for the endometrial proliferation.

Detection of Mast Cells and Basophils by Immunohistochemistry

Staining cells or tissues with basic dyes was the mainstay of mast cell and basophil detection methods for more than a century following the first identification of these cell types using such methods. These techniques have now been largely supplanted by immunohistochemical procedures with monoclonal antibodies directed against unique constituents of these cell types. Immunohistochemistry with antibodies specific for the granule protease tryptase provides a more sensitive and discriminating means for detecting mast cells than using the classical histochemical procedures; and employing antibodies specific for products of basophils (2D7 antigen and basogranulin) has allowed detection of basophils that infiltrate into tissues. The application of immunohistochemistry to detect more than one marker in the same cell has underpinned concepts of mast cell heterogeneity based on differential expression of chymase and other proteases. The double-labelling procedures employed have also provided a means for investigating the expression of cytokines and a range of other products. Protocols are here set out that have been used for immunohistochemical detection of mast cells and basophils and their subpopulations in human tissues. Consideration is given to pitfalls to avoid and to a range of alternative approaches.

Adipocytes spectrum — From homeostasia to obesity and its associated pathology

Firstly identified by anatomists, the fat tissue is nowadays an area of intense research due to increased global prevalence of obesity and its associated diseases. Histologically, there are four types of fat tissue cells which are currently recognized (white, brown, beige, and perivascular adipocytes). Therefore, in this study we are reviewing the most recent data regarding the origin, structure, and molecular mechanisms involved in the development of adipocytes. White adipocytes can store triglycerides as a consequence of lipogenesis, under the regulation of growth hormone or leptin and adiponectin, and release fatty acids resulted from lipolysis, under the regulation of the sympathetic nervous system, glucocorticoids, TNF-α, insulin, and natriuretic peptides. Brown adipocytes possess a mitochondrial transmembrane protein thermogenin or UCP1 which allows heat generation. Recently, thermogenic, UCP positive adipocytes have been identified in the subcutaneous white adipose tissue and have been named beige adipocytes. The nature of these cells is still controversial, as current theories are suggesting their origin either by transdifferentiation of white adipocytes, or by differentiation from an own precursor cell. Perivascular adipocytes surround most of the arteries, exhibiting a supportive role and being involved in the maintenance of intravascular temperature. Thoracic perivascular adipocytes resemble brown adipocytes, while abdominal ones are more similar to white adipocytes and, consequently, are involved in obesity-induced inflammatory reactions. The factors involved in the regulation of adipose stem cells differentiation may represent potential pathways to inhibit or to divert adipogenesis. Several molecules, such as pro-adipogenic factors (FGF21, BMP7, BMP8b, and Cox-2), cell surface proteins or receptors (Asc-1, PAT2, P2RX5), and hypothalamic receptors (MC4R) have been identified as the most promising targets for the development of future therapies. Further investigations are necessary to complete the knowledge about adipose tissue and the development of a new generation of therapeutic tools based on molecular targets.

The Immunohistochemical Assessment of HPV Related Adenocarcinoma: Pathologic and Clinical Prognostic Significance

Although several epidemiologic studies have confirmed the association between high-risk human papillomavirus (hr-HPV) and adenocarcinoma of the cervix, there are few papers focusing on the molecular immunophenotype of the HPV related cervical adenocarcinoma and its precursor lesions. The present study is aimed to assess the immunohistochemical expression of p16, p53, cyclin D1, EGFR, and COX-2 in benign and malignant lesions of cervical glandular components, and consequently the identification of the relationship between these markers and the HPV L1 capsid protein. We investigated 7 cases of endocervical adenocarcinoma in situ (AIS), 8 cases of adenosquamous carcinoma, 15 cases of invasive adenocarcinoma of endocervical type, and 5 cases without malignant lesions (normal and/or benign endocervical epithelium). The tissue fragments underwent standard laboratory procedures for the histopathological and immunohistochemical exams. For each marker, the semi-quantitative assessment was performed using appropriate scoring systems. Our results showed that: (i) the combination of L1 capsid protein and p16 can predict the progression risk of precursor lesion of endocervical adenocarcinomas; (ii) p53 - COX2 - p16 co-assessment is useful as a panel of relevant biomarkers for L1 - p16 association; (iii) EGFR increases according to the progression in lesions severity; (iv) cyclin D1 is a reliable marker for the invasive capacity. Further studies are necessary to quantify the value of these markers, as prognostic factors in HPV related cervical adenocarcinoma.

Multiple primary malignant neoplasms — case report

The synchronous occurence of primary carcinomas of endometrium and ovary is well recognized. Malignant peripheral nerve sheath tumours (MPNSTs) may also rarely occur in patients diagnosed with malignancies of the female genital tract. We report a rare case of synchronous primary carcinomas of endometrium and ovary, followed by a metachronous retroperitoneal MPNST. Ascites cytology and endometrial biopsy, followed by hysterectomy and bilateral adnexectomy, were performed to remove the synchronous tumors. Histology was suggestive of synchronous endometrial endometrioid carcinoma and ovarian mucinous adenocarcinoma. After the removal of the retroperitoneal tumor, a MPNST was diagnosed by immunohistochemistry. The patient developed two consecutive vaginal tumors diagnosed as metastases of the previously diagnosed endometrial carcinoma. Although synchronous tumors of endometrium and ovary were relatively early staged and consequently had a favorable prognosis, subsequently occuring implants along the lower genital tract and the metachronous MPNST added up to a poor prognosis.

Complex Mechanisms of Matrix Metalloproteinases Involvement in Endometrial Physiology and Pathology—An Update

Matrix metalloproteinases (MMPs) belong to a multigenic family of proteolytic enzymes with great structural variability which provide a complex intervention in pathophysiological conditions. Our review is focused on both MMPs key role in physiological reproductive events, such as embryo implantation, uterine involution, normal endometrial cycle, and on their role in the main endometrial pathologies. MMPs activity is closely regulated by tissue inhibitors of MMPs (TIMPs). MMP: TIMP imbalance has been incriminated in various pathological conditions, including endometrial cancer and endometriosis. Accumulated data support the involvement of a large spectrum of MMPs and TIMPs in endometrial carcinogenesis. Strong MMP-2 and weak TIMP-2 tissue immunoexpressions have a powerful prognosis value, while MMP-9 high expression suggests its important involvement in endometrial tumor invasiveness. Endometriosis development implies an accumulation of events showing partial overlap with endometrial carcinogenesis and invasion, requiring MMPs involvement. Therefore, increased levels of several MMPs have been detected in peritoneal fluid and/or endometrial tissue of patients diagnosed with endometriosis. Endometriotic mesenchymal stem cells (MSCs) may be involved in the pathogenesis of endometriosis due to their upregulated expression for markers of migration and angiogenesis, such as MMP-2, MMP-3, MMP-9, and VEGF. The hypothesis of therapeutic benefits of synthetic MMPs inhibitors, added to the progesterone or progestins action, has been based on the complex MMPs involvement in endometrial pathology. Future research is necessary to elucidate the complex interactions between molecules involved in proliferation, angiogenesis and apoptosis, opening new perspectives in the early diagnosis and treatment of endometrial neoplasia and endometriosis.

Heterogeneous Periostin Expression in Different Histological Variants of Papillary Thyroid Carcinoma

Background Periostin (PN) epithelial and stromal overexpression in tumor pathology has been studied according to tumor growth, angiogenesis, invasiveness, and metastasis, but a limited number of studies address PN in thyroid tumors. Aim Our study aimed to analyze PN expression in different histological variants of PTC and to correlate its expression with the clinicopathological prognostic factors. Material and Methods PN expression has been immunohistochemically assessed in 50 cases of PTC (conventional, follicular, oncocytic, macrofollicular, and tall cell variants), in tumor epithelial cells and intratumoral stroma. The association between PN expression and clinicopathological characteristics has been evaluated. Results Our results show that PTC presented different patterns of PN immunoreaction, stromal PN being significantly associated with advanced tumor stage and extrathyroidal extension. No correlations were found between PN overexpression in tumor epithelial cells and clinicopathological features, except for specific histological variants, the highest risk of poor outcome being registered for the conventional subtype in comparison to the oncocytic type. Conclusions Our study demonstrates differences in PN expression in histological subtypes of PTC. Our results plead in favor of a dominant protumorigenic role of stromal PN, while the action of epithelial PN is less noticeable.

Periostin in bronchial asthma – a brief update

Periostin is an extracellular matrix protein which intervenes in the regulation of angiogenesis, and in tumoral cells proliferation and invasion. Recent studies, mainly experimental models, have demonstrated the intervention of this molecule in asthmatic disease, by eosinophils recruitment, bronchial wall remodeling, and by stimulation of inflammatory cytokines production. Currently, periostin is considered a marker of type 2 inflammation in asthma, being secreted by respiratory epithelial cells triggered by IL-13 and IL-4. Concomitantly, periostin accumulated at the bronchial epithelial-connective tissue interface is involved in fibrogenesis and mucus secretion, in correlation with the intensity of bronchial mucosa eosinophilic inflammatory infiltrate. However, the intimate molecular mechanisms of periostin involvement in the pathogenic pathway of asthmatic diseases is far away from elucidation, further research being necessary to certify its value as a biomarker useful in diagnosis and in establishment of therapeutic schemes in bronchial asthma.