Nader Husseinzadeh

Macrophages Mediate Inflammation-Enhanced Metastasis of Ovarian Tumors in Mice

The tumor microenvironment is known to have a profound effect on tumor progression in a highly context-specific manner. We have investigated whether peritoneal inflammation plays a causative role in ovarian tumor metastasis, a poorly understood process. Implantation of human ovarian tumor cells into the ovaries of severe combined immunodeficient mice resulted in peritoneal inflammation that corresponds temporally with tumor cell dissemination from the ovaries. Enhancement of the inflammatory response with thioglycolate accelerated the development of ascites and metastases. Suppression of inflammation with acetyl salicylic acid delayed ascites development and reduced tumor implant formation. A similar prometastatic effect for inflammation was observed when tumor cells were injected directly into the peritoneum of severe combined immunodeficient mice, and in a syngeneic immunocompetent mouse model. Inflammation-modulating treatments did not affect primary tumor development or in vitro tumor cell growth. Depletion of peritoneal macrophages, but not neutrophils or natural killer cells, reduced tumor progression, as assessed by ascites formation and peritoneal metastasis. We conclude that inflammation facilitates ovarian tumor metastasis by a mechanism largely mediated by macrophages, and which may involve stromal vascular endothelial growth factor production. The confirmation of these findings in immunocompetent mice suggests relevance to human disease. Identifying the mechanisms by which macrophages contribute to tumor metastasis may facilitate the development of new therapies specifically targeting immune cell products in the tumor microenvironment.

Toll-like receptor expression in normal ovary and ovarian tumors

Recent studies have implicated inflammation in the initiation and progression of ovarian cancer, though the mechanisms underlying this effect are still not clear. Toll-like receptors (TLRs) allow immune cells to recognize pathogens and to trigger inflammatory responses. Tumor cell expression of TLRs can promote inflammation and cell survival in the tumor microenvironment. Here we sought to characterize the expression of TLRs in normal human ovaries, benign and malignant ovarian tumors from patients, and in established ovarian tumor cell lines. We report that TLR2, TLR3, TLR4, and TLR5 are strongly expressed on the surface epithelium of normal ovaries. In contrast to previous studies of uterus and endocervix, we found no cyclic variation in TLR expression occurred in murine ovaries. TLR2, TLR3, TLR4, and TLR5 are expressed in benign conditions, epithelial tumors, and in ovarian cancer cell lines. Variable expression of TLR6 and TLR8 was seen in benign and malignant epithelium of some patients, while expression of TLR1, TLR7, and TLR9 was weak. Normal and malignant ovarian stroma were negative for TLR expression. Vascular endothelial cells, macrophages, and occasional fibroblasts in tumors were positive. Functional activity for TLRs was demonstrated by stimulation of cell lines with specific ligands and subsequent activation and translocation of NFκB and release of the proinflammatory cytokines interleukin-6 and CCL-2. These studies demonstrate expression of multiple TLRs in the epithelium of normal ovaries and in ovarian tumor cells, and may indicate a mechanism by which epithelial tumors manipulate inflammatory pathways to facilitate tumor progression.

Predictive value of cone margins and post-cone endocervical curettage with residual disease in subsequent hysterectomy

In 51 of 106 patients (48%) residual disease was identified in hysterectomy specimens performed following cervical conization. Invasive squamous cell carcinoma was found in one patient in spite of clear cone margins. Thirty-nine of sixty-three patients (62%) with cervical intraepithelial neoplasia (CIN) involving the inner (endocervical) margin of the cone biopsy had residual disease. When both the inner margin and post-cone endocervical curettage (ECC) were involved, residual disease was present in 24 of 30 (80%) hysterectomy specimens. When the inner margins of the cone were involved with CIN-III and the post-cone ECC was negative, 36% of hysterectomy specimens contained residual disease compared to 88% when post-cone ECC was positive. These findings indicate that post-cone endocervical curettage has significant predictive value with respect to the presence or absence of residual disease in patients with CIN involving the inner margins of the cervical cone.

DEK Proto-Oncogene Expression Interferes with the Normal Epithelial Differentiation Program

Overexpression of the DEK gene is associated with multiple human cancers, but its specific roles as a putative oncogene are not well defined. DEK transcription was previously shown to be induced by the high-risk human papillomavirus (HPV) E7 oncogene via E2F and Rb pathways. Transient DEK overexpression was able to inhibit both senescence and apoptosis in cultured cells. In at least the latter case, this mechanism involved the destabilization of p53 and the decreased expression of p53 target genes. We show here that DEK overexpression disrupts the normal differentiation program in a manner that is independent of either p53 or cell death. DEK expression was distinctly repressed upon the differentiation of cultured primary human keratinocytes, and stable DEK overexpression caused epidermal thickening in an organotypic raft model system. The observed hyperplasia involved a delay in keratinocyte differentiation toward a more undifferentiated state, and expansion of the basal cell compartment was due to increased proliferation, but not apoptosis. These phenotypes were accompanied by elevated p63 expression in the absence of p53 destabilization. In further support of bona fide oncogenic DEK activities, we report here up-regulated DEK protein levels in both human papilloma virus-positive hyperplastic murine skin and a subset of human squamous cell carcinomas. We suggest that DEK up-regulation may contribute to carcinoma development at least in part through increased proliferation and retardation of differentiation.

Epithelial Alterations in Proximity to Invasive Squamous Carcinoma of the Vulva

Summary The histologic changes within epithelium adjacent to invasive carcinomas theoretically may include the specific lesions that precede the development of the invasive neoplasm, or may reflect the response of host epithelium to the carcinoma or to nonspecific inflammatory stimuli related to ulceration and tissue necrosis. We have studied the vulvar epithelium surrounding squamous carcinomas of 60 women undergoing vulvectomy to determine the frequency and type of potential precursor lesions and their relationship to various biologic parameters. Using modified criteria and nomenclature of the International Society for the Study of Vulvar Disease, we identified some degree of nuclear atypia (either atypical hyperplastic dystrophy or carcinoma in situ) in 72% of patients; in only 3% was there a direct transition from normal epithelium to invasive carcinoma. There was no apparent relationship between the presence of atypia and histologic grade, depth of invasion, size or stage of tumor, or frequency of nodal metastasis. Although direct evidence is lacking, these atypical lesions may serve to identify a population at increased risk for subsequent development of invasive carcinoma.

Status of tumor markers in epithelial ovarian cancer has there been any progress? A review

OBJECTIVE The aim is to present an overview of tumor markers other than CA-125 that have been proposed for use in the diagnosis of epithelial ovarian cancer and explore molecular studies which have been used to identify genomic and proteomic changes associated with this malignancy for possible future development of more sensitive tumor markers. METHODS A Medline search was conducted to review published articles from American and European studies from 1990 to 2010, related to tumor markers for ovarian cancer. Different methods such as genomic, proteomic and transcriptional profiling were used to identify new tumor markers for clinical use. RESULTS A few of the newer tumor markers alone have demonstrated equal or slightly higher sensitivity to CA-125. Improved sensitivity and specificity have been reported using these new markers combined with CA-125. CONCLUSION Addition of new tumor markers as a compliment to CA-125 were associated with higher sensitivity and detection rates than either marker alone. However, the low prevalence of ovarian cancer necessitates a higher level of sensitivity and specificity that has still not been achieved if these biomarkers are used for diagnosis and monitoring the disease progress as a result of low positive predictive value.

Metastatic female adnexal tumor of probable wolffian origin : A case report and review of the literature

Female adnexal tumor of probable wolffian origin is a rare neoplasm that can present diagnostic difficulties. We report herein a case of a 60-year-old woman with female adnexal tumor of probable wolffian origin arising within the leaves of a broad ligament and, 5 years later, presenting with metastasis to the liver. The morphologic, immunohistochemical, ultrastructural, and DNA ploidy findings of the original and metastatic tumor, differential diagnoses, and the results of the English-language literature review are presented.

The prognostic significance of vascular channel involvement and deep stromal penetration in early cervical carcinoma.

EIGIITY-EIGHT PATIENTS WITH FIGO Stage Ib and IIa squamous cell carcinoma of the cervix underwent radical hysterectomy with pelvic and paraaortic lymphadenectomy. The records and histopathologic material were reviewed to determine the prognostic significance of vascular channel involvement and deep stromal penetration by tumor. Seventy-four patients (84%) were alive and free of disease for more than 2 years and 14 (16%) developed recurrent carcinoma within that time. A positive correlation was found between depth of stromal penetration by tumor and the degree of vascular channel involvement (p <0.05). Vascular involvement in itself did not significantly affect nodal status, survival or the rate of recurrence. Depth of penetration was associated with a higher incidence of positive nodes (p <0.05). There was a trend towards a lower survival rate and a higher recurrence rate in patients with deep stromal penetration as compared to those with superficial tumors. Microscopic nodal disease increased the rate of recurrence and had an adverse effect on survival. The combination of deep tumor penetration and positive nodes in the same patient was associated with the highest recurrence rate and the lowest survival (p <0.05). Nodal status was a more significant prognostic indicator than depth of tumor penetration because patients with deeply penetrating tumors and positive nodes had more than twice the recurrence rate than did patients with deep tumors and negative nodes. Postoperative radiation therapy was beneficial to patients whose tumors demonstrated deep stromal penetration and microscopic metastases to pelvic lymph nodes.

Role of Toll-like receptors in cervical, endometrial and ovarian cancers: A review

OBJECTIVE The Toll-like receptors (TLRs) have been implicated in inflammation, innate immunity and cancer. The goal of this paper is to review the available published research about Toll-like receptors and their roles in gynecologic malignancies. METHODS A Medline search was conducted and published articles from the late 1990s to the present (2014) were reviewed using search phrases, Toll-like receptors and cervical, endometrial and ovarian cancers. RESULTS TLR4 and TLR5 are commonly absent in normal cervix, however TLR5 expression is strong in high grade cervical dysplasia as well as invasive cancer. The expression of TLR3 and TLR4 is low in endometrial cancer. TLR2, TLR3, TLR4 and TLR5 are highly expressed in normal and neoplastic ovarian epithelium. TLR3 has been shown to have a dual function: it can contribute to tumor elimination by upregulation of interferons α and β (INF) and natural killer cell (NK) activation or it can indirectly contribute to tumor progression. CONCLUSIONS Inflammation is an essential element in tumorigenesis. Toll-like receptors can trigger an inflammatory response and cell survival in the tumor micro-environment. TLRs are critical immunomodulators that may play an important role in the development of gynecologic cancers. Currently TLR agonists are being investigated for a potential role as an adjuvant in the treatment of gynecologic malignancies.

Vulvar intraepithelial neoplasia: A clinicopathological study of carcinoma in situ of the vulva

Thirty-two patients with carcinoma in situ of the vulva were analyzed with respect to age-specific incidence rates, associated human papilloma virus (koilocytosis and condyloma) changes, and multifocal, unifocal distribution of the lesions. The association of koilocytosis and condyloma changes in the neoplastic epithelium correlated with a younger mean age compared to those without human papilloma virus (HPV) changes (39 versus 67 years). Also, patients with multifocal disease were found to have a younger mean age compared to those with unifocal disease (31 versus 61 years). Carcinoma in situ of the vulva appears to be a disease that affects two patient population groups. Patients with coexistent HPV infection usually are younger and have multifocal disease, and those patients with a variable history of HPV infection usually are older and have unifocal disease.