Abstract A64: Association of interleukin 16 with early metastasis of ovarian tumors
Authors: Yellapa Aparna , Bitterman Pincas , Abramowicz Jacques S. , Bahr Janice M. , Sharma Sameer , Basu Sanjib , Barua Animesh 
Published: August 2014

Introduction: Ovarian cancer (OVCA) differs from other malignancies in its specific dissemination pattern that the tumor typically spreads in a diffuse intra-abdominal fashion rather than systemic circulation. Interactions among different cell types and their secretory products in the tumor microenvironment may contribute to the tumor development and metastasis. Interleukin 16 (IL-16) is a chemoattractant and pro-angiogenic cytokine involved in multiple immunopathobiological processes. IL-16 is expressed by several cell types including CD8 T cells and macrophages and occasionally by malignant cells. IL-16 expression is reported to be increased in several tumors including OVCA. Thus, IL-16 may be involved in the development and metastasis of ovarian tumors, if so, how IL-16 enhances tumor metastasis is not known. CD9, a member of tetraspanin family, has been implicated in the regulation of cell proliferation, invasion and motility. Emerging studies reported CD9 as a receptor for IL-16.

Objectives: The goal of this study was to determine (1) whether IL-16 is associated with ovarian tumor metastasis in the vicinity of tumors including the omentum and (2) if so, to determine how IL-16 is associated with ovarian tumor metastasis. In this study we examined association of IL-16 and its receptor (CD9) expression with respect to ovarian tumor development and progression. The association of CD8+T cells and IL-16 expression during tumor initiation was examined in laying hens, an animal model of spontaneous OVCA.

Methods: Experiment-1: Tumor specimen from patients with serous OVCA (10 early and 20 late stages), serous benign ovarian tumors (n=10) and normal (n=5, from patients underwent hysterectomies for non-ovarian disease) and omental tissues (n= 5, each of OVCA and benign) were used. Changes in IL-6 and CD9 expression in tumor tissues (ovaries and omentum) were examined by immunohistochemistry, proteomics and by quantitative polymerase chain reaction (qPCR). Experiment-II: Laying hens with normal ovaries (n=10) or microscopic OVCA (n=10) were examined for CD8 T cells and IL-16 expressing cells as mentioned above. The correlation between the IL-16 and CD8+ T cells were examined. In addition, to examine the effects of IL-16 on CD9 expression, normal ovarian surface epithelial (OSE) cells were treated with recombinant IL-16 protein.

Results: Compared with normal ovaries and benign tumors, the frequencies of IL-16 expressing cells were significantly high in early stage OVCA (P&lt;0.01) and increased further in late stage OVCA. Compared with primary ovarian tumors, the population of IL-16 expressing cells was remarkably high in omental tissues containing tumor (P&lt;0.01). Similarly, compared with normal, intense staining was observed for CD9 expression both in malignant ovarian and omental tissues. CD9 staining intensities were positively correlated with the increased frequency of IL-16 expressing cells. Recombinant IL-16 treatment of OSE enhanced CD9 expression suggesting the stimulatory effects of IL-16 on CD9 expression. Compared with normal hens, frequency of CD8+ T cells increased significantly in hens with microscopic OVCA. Similarly, compared with normal hens, the population of IL-16 expressing cells increased significantly in hens with microscopic OVCA. The frequency of IL-16 expressing cells was positively correlated with the frequency of CD8+ T cells.

Conclusions: The results of the present study suggest that increased IL-16 expression may be associated with enhanced CD9 expression which may be a factor for ovarian tumor progression and metastasis to the omental tissues. Increased CD8+ T cells in the tumor vicinity suggests that CD8+ T cells may be a source of enhanced IL-16 expression in developing ovarian tumors.

Support: DOD award # W81XWH-11-1-0510

Citation Format: Aparna Yellapa, Pincas Bitterman, Jacques S. Abramowicz, Janice M. Bahr, Sameer Sharma, Sanjib Basu, Animesh Barua. Association of interleukin 16 with early metastasis of ovarian tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A64.