CD44 Regulates Formation of Spheroids and Controls Organ-Specific Metastatic Colonization in Epithelial Ovarian Carcinoma.

Disseminating epithelial ovarian cancer cells often become assembled into spheroids prior to their arrival at metastatic sites within the peritoneal cavity. Although epithelial ovarian carcinoma (EOC) is the deadliest gynecologic malignancy, the mechanisms regulating formation and metastatic potential of spheroids are poorly understood. We show that expression of a cell surface glycoprotein CD44 is an important contributing factor for spheroid formation and spheroid adhesion to mesothelial cells, and its loss impairs mesenteric metastasis. In contrast, loss of CD44 resulted in significant increase of tumor burden at several locoregional sites, including liver, and unleashed distant metastases to the thoracic cavity. Altogether our studies suggest that CD44 regulates metastatic progression of EOC in an organ-specific manner. IMPLICATIONS: Expression of CD44 promotes spheroid formation, mesothelial adhesion, and formation of mesenteric metastasis, but it suppresses development of metastasis to several peritoneal sites, including liver, and the thoracic cavity.

Inflammation on Prostate Needle Biopsy is Associated with Lower Prostate Cancer Risk: A Meta-Analysis.

PURPOSE: We performed a comprehensive literature review and meta-analysis to evaluate the association of inflammation on prostate needle biopsies and prostate cancer risk. MATERIALS AND METHODS: We searched Embase®, PubMed® and Web of Science™ from January 1, 1990 to October 1, 2016 for abstracts containing the key words prostate cancer, inflammation and biopsy. Study inclusion criteria were original research, adult human subjects, cohort or case-control study design, histological inflammation on prostate needle biopsy and prostate cancer on histology. Two independent teams reviewed abstracts and extracted data from the selected manuscripts. Combined ORs and 95% CIs of any, acute and chronic inflammation were calculated using the random effects method. RESULTS: Of the 1,030 retrieved abstracts 46 underwent full text review and 25 were included in the final analysis, comprising a total of 20,585 subjects and 6,641 patients with prostate cancer. There was significant heterogeneity among studies (I2 = 84.4%, p <0.001). The presence of any inflammation was significantly associated with a lower prostate cancer risk in 25 studies (OR 0.455, 95% CI 0.337-0.573). There was no evidence of publication bias (p >0.05). When subanalyzed by inflammation type, acute inflammation in 4 studies and chronic inflammation in 15 were each associated with a lower prostate cancer risk (OR 0.681, 95% CI 0.450-0.913 and OR 0.499, 95% CI 0.334-0.665, respectively). CONCLUSIONS: In a meta-analysis of 25 studies inflammation on prostate needle biopsy was associated with a lower prostate cancer risk. Clinically the presence of inflammation on prostate needle biopsy may lower the risk of a subsequent prostate cancer diagnosis.

The Development of Prostate Adenocarcinoma in a Transgender Male to Female Patient: Could Estrogen Therapy Have Played a Role?

BACKGROUND: Prostate adenocarcinoma (PCa) is a rare diagnosis in the male to female transgender (MtFT) population with only a few case reports published in the current medical literature. Long standing beliefs of androgen suppression conferring a protective effect against prostate cancer development have been challenged by the literature citing adenocarcinoma development in the prostate of rodent models following combined estrogen and testosterone treatment. MATERIALS AND METHODS: We herein present a MtFT patient who presented with high grade PCa following 20 years of exogenous estrogen therapy. RESULTS: Immunohistochemical (IHC) localization of estrogen receptor alpha (ER-α) and progesterone receptor (PR) demonstrated positive staining in stromal cells; while, androgen receptor (AR) demonstrated positive staining in malignant glands and weak scattered staining in adjacent stroma. CONCLUSION: This pattern of staining raises concern for a possible contributing role of exogenous estrogen therapy in tumorigenesis. As awareness of gender dysphoria and acceptance of gender reassignment surgery has seen a recent increase, the unique needs of this population must be recognized. Prostate 77:824-828, 2017. © 2017 Wiley Periodicals, Inc.

Examination of the Fractalkine and Fractalkine Receptor Expression in Fallopian Adenocarcinoma Reveals Differences When Compared to Ovarian Carcinoma.

Fallopian adenocarcinoma is a rare malignancy arising in the epithelium of the fallopian tube. Fallopian tube epithelium has been proposed as a tissue origin for high-grade serous ovarian carcinoma, the deadliest gynecologic malignancy. Given the commonalities in dissemination and treatment of these malignancies, we contemplated the possibility of similar patterns of gene expression underlying their progression. To reveal potential similarities or differences in the gene expression of fallopian adenocarcinoma and high-grade serous ovarian carcinoma, we tested expression of the fractalkine receptor (CX3CR1) and its ligand, fractalkine (CX3CL1), in the specimens of normal and pathologic fallopian tube using immunohistochemistry. Our data show that CX3CR1 is expressed in the normal, cancer adjacent normal, inflammatory, and malignant fallopian epithelium. CX3CL1 was expressed only by the normal and cancer adjacent normal fallopian tube epithelium; its expression was largely lost in the inflammatory and malignant fallopian epithelium. In opposite, both CX3CR1 and CX3CL1 are expressed in high-grade serous ovarian carcinoma. These findings are consistent with an idea that fallopian adenocarcinoma and high-grade serous ovarian carcinoma, although currently thought to arise from the same organ, may not share similar molecular characteristics.

Three-dimensional collagen type I matrix up-regulates nuclear isoforms of the microtubule associated protein tau implicated in resistance to paclitaxel therapy in ovarian carcinoma.

Epithelial ovarian carcinoma is the deadliest gynecologic malignancy. One reason underlying treatment failure is resistance to paclitaxel. Expression of the microtubule associated protein tau has recently been proposed as a predictor of response to paclitaxel in ovarian carcinoma patients. Expression of tau was probed using immunohistochemistry in 312 specimens of primary, and 40 specimens of metastatic, ovarian carcinoma. Serous epithelial ovarian carcinoma cell line models were used to determine the expression of tau by Western blot and immunofluorescence staining. Subcellular fractionation and Western blot were employed to examine nuclear and cytoplasmic localization of tau. Gene silencing and clonogenic assays were used to evaluate paclitaxel response. Tau was expressed in 44% of all tested cases. Among the primary serous epithelial ovarian carcinoma cases, 46% were tau-positive. Among the metastatic serous epithelial ovarian carcinomas, 63% were tau-positive. Cell culture experiments demonstrated that tau was expressed in multiple isoforms. Three-dimensional collagen I matrix culture conditions resulted in up-regulation of tau protein. Silencing of tau with specific siRNAs in a combination with three-dimensional culture conditions led to a significant decrease of the clonogenic ability of cells treated with paclitaxel. The data suggest that reduction of tau expression may sensitize ovarian carcinoma to the paclitaxel treatment.

Fractalkine receptor is expressed in mature ovarian teratomas and required for epidermal lineage differentiation.

BACKGROUND: The goal of this study was to determine a predominant cell type expressing fractalkine receptor (CX3CR1) in mature ovarian teratomas and to establish functional significance of its expression in cell differentiation. METHODS: Specimens of ovarian teratoma and human fetal tissues were analyzed by immunohistochemistry for CX3CR1expression. Ovarian teratocarcinoma cell line PA-1 was used as a model for cell differentiation. RESULTS: We found that the majority of the specimens contained CX3CR1-positive cells of epidermal lineage. Skin keratinocytes in fetal tissues were also CX3CR1- positive. PA-1 cells with downregulated CX3CR1 failed to express a skin keratinocyte marker cytokeratin 14 when cultured on Matrigel in the presence of a morphogen, bone morphogenic protein 4 (BMP-4), as compared to those expressing scrambled shRNA. CONCLUSIONS: Here we demonstrate that CX3CR1 is expressed in both normally (fetal skin) and abnormally (ovarian teratoma) differentiated keratinocytes and is required for cell differentiation into epidermal lineage.

Matrix rigidity activates Wnt signaling through down-regulation of Dickkopf-1 protein.

Cells respond to changes in the physical properties of the extracellular matrix with altered behavior and gene expression, highlighting the important role of the microenvironment in the regulation of cell function. In the current study, culture of epithelial ovarian cancer cells on three-dimensional collagen I gels led to a dramatic down-regulation of the Wnt signaling inhibitor dickkopf-1 with a concomitant increase in nuclear ß-catenin and enhanced ß-catenin/Tcf/Lef transcriptional activity. Increased three-dimensional collagen gel invasion was accompanied by transcriptional up-regulation of the membrane-tethered collagenase membrane type 1 matrix metalloproteinase, and an inverse relationship between dickkopf-1 and membrane type 1 matrix metalloproteinase was observed in human epithelial ovarian cancer specimens. Similar results were obtained in other tissue-invasive cells such as vascular endothelial cells, suggesting a novel mechanism for functional coupling of matrix adhesion with Wnt signaling.

The lymphotactin receptor is expressed in epithelial ovarian carcinoma and contributes to cell migration and proliferation.

Chemokine receptor-ligand interactions are important to support functioning of both normal and pathologic cells. The expression and function of chemokine receptors in epithelial ovarian carcinoma (EOC) is largely unknown. Here, we report that the lymphotactin receptor (XCR1) was expressed in primary and metastatic human epithelial ovarian carcinoma (EOC) specimens and cell lines. In contrast, expression of XCR1 was not detected in the normal ovary or in human normal ovarian surface epithelial cells. Our data indicate that XCL1 and XCL2 are either present in the malignant ascites or expressed by the ovarian carcinoma cells. The addition of lymphotactin (XCL1 and XCL2) stimulated migration and proliferation of XCR1-positive cells. Reduction of XCR1 expression in ovarian carcinoma cell line SKOV-3 resulted in abrogated diaphragm and peritoneal wall tumor formation and in reduced frequency of colonic, splenetic, and liver nodules in an in vivo xenograft mouse model. Taken together, our data suggest that XCR1 is expressed early during the course of tumorigenic transformation and contributes towards increased cell migration and proliferation, which can facilitate the prometastatic behavior of EOC cells.

Fractalkine receptor CX(3)CR1 is expressed in epithelial ovarian carcinoma cells and required for motility and adhesion to peritoneal mesothelial cells.

Epithelial ovarian carcinoma (EOC) is a deadly disease, and little is known about the mechanisms underlying its metastatic progression. Using human specimens and established cell lines, we determined that the G-protein-coupled seven-transmembrane fractalkine receptor (CX(3)CR1) is expressed in primary and metastatic ovarian carcinoma cells. Ovarian carcinoma cells robustly migrated toward CX(3)CL1, a specific ligand of CX(3)CR1, in a CX(3)CR1-dependent manner. Silencing of CX(3)CR1 reduced migration toward human ovarian carcinoma ascites fluid by approximately 70%. Importantly, adhesion of ovarian carcinoma cells to human peritoneal mesothelial cells was dependent on CX(3)CL1/CX(3)CR1 signaling. In addition, CX(3)CL1 was able to induce cellular proliferation. Together, our data suggest that the fractalkine network may function as a major contributor to the progression of EOC, and further attention to its role in the metastasis of this deadly malignancy is warranted.

Prostate cancer outcome and tissue levels of metal ions.

BACKGROUND: There are several studies examining prostate cancer and exposure to cadmium, iron, selenium, and zinc. Less data are available on the possible influence of these metal ions on prostate cancer outcome. This study measured levels of these ions in prostatectomy samples in order to examine possible associations between metal concentrations and disease outcome. METHODS: We obtained formalin fixed paraffin embedded tissue blocks of prostatectomy samples of 40 patients with PSA recurrence, matched 1:1 (for year of surgery, race, age, Gleason grading, and pathology TNM classification) with tissue blocks from 40 patients without recurrence (n = 80). Case-control pairs were compared for the levels of metals in areas adjacent to tumors. Inductively coupled plasma-mass spectrometry (ICP-MS) was used for quantification of Cd, Fe, Zn, and Se. RESULTS: Patients with biochemical (PSA) recurrence of disease had 12% lower median iron (95 µg/g vs. 111 µg/g; P = 0.04) and 21% lower zinc (279 µg/g vs. 346 µg/g; P = 0.04) concentrations in the normal-appearing tissue immediately adjacent to cancer areas. Differences in cadmium (0.489 µg/g vs. 0.439 µg/g; 4% higher) and selenium (1.68 µg/g vs. 1.58 µg/g; 5% higher) levels were not statistically significant in recurrence cases, when compared to non-recurrences (P = 0.40 and 0.21, respectively). CONCLUSIONS: There is an association between low zinc and low iron prostate tissue levels and biochemical recurrence in prostate cancer. Whether these novel findings are a cause or effect of more aggressive tumors, or whether low zinc and iron prostatic levels raise implications for therapy, remains to be investigated.

Tissue microarrays from biopsy specimens.

The construction of tissue microarrays from needle core biopsy specimens allows for the study of diseases with limited tissue samples and provides insight into tumors that are treated with nonsurgical approaches. While the techniques are technically challenging, in the hands of investigators they can reveal new insights into biomarkers of disease.

The progress on genetic analysis of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world, but is one of the most common cancers in Southeast Asia. Both genetic and environmental factors contribute to the tumorigenesis of NPC, most notably the consumption of certain salted food items and Epstein-Barr virus infection. This review will focus on the current progress of the genetic analysis of NPC (genetic susceptibilities and somatic alterations). We will review the current advances in genomic technologies and their shaping of the future direction of NPC research.

Prostate cancer in patients with screening serum prostate specific antigen values less than 4.0 ng/dl: results from the cooperative prostate cancer tissue resource.

PURPOSE: Prostate cancer can occur in patients with low screening serum prostate specific antigen (PSA) values (less than 4.0 ng/ml). It is currently unclear whether these tumors are different from prostate cancer in patients with high PSA levels (greater than 4.0 ng/ml). MATERIALS AND METHODS: From the Cooperative Prostate Cancer Tissue Resource database through March 2004, 3,416 patients with screening PSA less than 16.0 ng/ml diagnosed with prostate cancer between 1993 and 2004 were stratified in groups based on screening serum PSA. These subsets were compared for race, age at diagnosis, clinical and pathological stage, Gleason score, positive surgical margins, posttreatment recurrent disease, and vital status. RESULTS: We identified 468 (14%) patients with screening PSA less than 4.0 ng/ml, 142 (4.2%) of whom had a PSA of less than 2.0 ng/ml. This group included 40 black and 376 white patients. Men with low screening PSA treated with radical prostatectomy had smaller cancers, lower Gleason scores, lower pathological tumor (T) stage and lower PSA recurrence rates than men with high PSA levels (4 ng/ml or greater). These differences held true for men who were younger than 62 years or were white, whereas older or black men had tumor characteristics and outcomes similar to those with higher PSA levels. CONCLUSIONS: Young (younger than 62 years) or white patients with screening serum PSA less than 4.0 ng/ml had smaller, lower grade tumors and lower recurrence rates than patients with PSA 4.0 ng/ml or greater. This was not true for those older than 62 years and for black men.

Simple, inexpensive method for automating tissue microarray production provides enhanced microarray reproducibility.

Tissue microarrays are a novel technology with the potential to impact cancer research by reducing the time, materials, and costs related to specimen-based marker validation. The process uses small cores of specimen tissue for molecular studies, maximizing the quantity of specimens that can be analyzed on a single slide and the results that can be obtained from a single antibody study. However, this process can be tedious and requires a significant time commitment for array production, particularly for the hand-produced tissue array blocks. In addition, this process has significant repetitive motions, risking repetitive stress injury for technical personnel. For these reasons, we have sought a simple, inexpensive system for automation of the existing microarray technologies. Using this system, slides containing as many as 400 specimens can be constructed in a simple and reproducible manner. Automation of the tissue microarray apparatus is accomplished by attaching two stepper motors to the micrometers of the apparatus that control array movement, and it has the advantages of standardizing the spacing between each specimen and eliminating repetitive motions by the user. A computer program is used to run the motors, allowing the user to input commands based on the desired moving distance. After assimilation of the motors, motor control boards, and corresponding program, the final product was tested and demonstrated to provide consistent, reproducible operation. Tissue microarrays were generated with specimen tissue diameters of 1.5 mm, 1.0 mm, and 0.6 mm with core densities upwards of 300 samples per slide.

Efeito talidomida sobre os níveis séricos de imunoglobulinas IgM e IgA, fator reumatóide e isohemaglutinina anti-A e Anti-B em pacientes com lepra lepromatosa: estudo duplo-cego / Effect of thalidomide on serum levels of imnunoglobulins IgM and IgA, rheumatoid factor and isohemagglutinis anti-A and anti-B in patients with lepromatosus leprosy: a double blind study

Um estudo duplo-cego foi conduzido em pacientes portadores de lepra lepromatosa estável, para avaliar a resposta a administraçäo de talidomida 100 mg por dia, por 18 dias, dos níveis séricos de IgM e IgA e dos títulos de fator reumatóide e isohemaglutininas anti-A e anti-B. Nenhum efeito significativo foi detectado ao fim deste período