Intracapsular and well-defined adenocarcinomas of the prostate are often surrounded by tissue areas that harbor molecular aberrations, including those of genetic, epigenetic and biochemical nature. This is known as field cancerization, or a field effect and denotes a state of pre-malignancy. Such alterations in histologically normal tumor-adjacent prostatic tissues have been recognized as clinically important and are potentially exploitable as biomarkers of disease and/or targets for preventative/therapeutic intervention. The authors have previously identified and validated two protein markers of field cancerization: The expressional upregulation of the transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FASN). However, the molecular etiology of prostate field cancerization, including EGR-1 and FASN upregulation, remains largely unknown. It was thus hypothesized that extracellular vesicles, notably exosomes, released by tumor lesions may induce molecular alterations in the surrounding tissues, resulting in field cancerization, priming the tissue, and ultimately promoting multifocal tumorigenesis, which is often observed in prostate cancer. Towards testing this hypothesis, the current study, to the best of our knowledge, for the first time, presents correlative protein expression data, generated in disease-free, tumor-adjacent and cancerous human prostate tissues by quantitative immunofluorescence, between the exosomal marker CD9, and EGR-1 and FASN. Despite the pilot character of the present study, and the static nature and heterogeneity of human tissues, the data suggest that CD9 expression itself is part of a field effect. In support of this hypothesis, the results suggest a possible contribution of exosomes to the induction of field cancerization in the prostate, particularly for EGR-1. These findings were corroborated in established cell models of cancerous (LNCaP) and non-cancerous (RWPE-1) human prostate epithelial cells. The findings of this study warrant further investigation into the functional interface between exosomes and field cancerization, as a detailed understanding of this characterization may lead to the development of clinical applications related to diagnosis and/or prognosis and targeted intervention to prevent progression from pre-malignancy to cancer.
One in 8 women will develop breast cancer in their lifetime. Yet, the burden of disease is greater in Black women. Black women have a 40% higher mortality rate compared to White women, and a higher incidence of breast cancer at age 40 and younger. While the underlying cause of this disparity is multifactorial, exposure to endocrine disrupting chemicals (EDCs) in hair and other personal care products has been associated with an increased risk of breast cancer. Parabens are known EDCs that are commonly used as preservatives in hair and other personal care products, and Black women are disproportionately exposed to products containing EDCs. Studies have shown that parabens impact breast cancer cell proliferation, death, migration/invasion, and metabolism, as well as gene expression in vitro. However, these studies were conducted using cell lines of European ancestry; to date, no studies have utilized breast cancer cell lines of West African ancestry to examine the effects of parabens on breast cancer progression. Like breast cancer cell lines with European ancestry, we hypothesize that parabens promote pro-tumorigenic effects in breast cancer cell lines of West African ancestry. Luminal breast cancer cell lines with West African ancestry (HCC1500) and European ancestry (MCF-7) were treated with biologically relevant doses of methylparaben, propylparaben, and butylparaben. Following treatment, estrogen receptor target gene expression and cell viability were examined. We observed altered estrogen receptor target gene expression and cell viability that was paraben- and cell-line specific. This study provides greater insight into the tumorigenic role of parabens in the progression of breast cancer in Black women.
Ovarian cancer (OvCa) is the fifth leading cause of cancer-related deaths among women and in the metastatic setting has only an 18% 5-year survival, illustrating the need for new therapeutic strategies to effectively treat the disease. Approximately 90% of epithelial ovarian cancers express tumor-associated glycoprotein 72 (TAG72), thus making it an effective target for the development of chimeric antigen receptor (CAR)-engineered T cell therapies. Our previous studies have demonstrated efficacy of TAG72-CAR T cells in reducing tumor growth and improving survival using in vivo human tumor xenograft mouse models; however, these models are limited in their ability to capture the effects of the immune system and the tumor microenvironment on the impact of CAR T cell therapy. Thus, we have established a novel spontaneous OvCa model using the hen to preclinically evaluate our TAG72-CAR T cell therapy. Hens are one of the only spontaneous preclinical animal models for OvCa, because naturally occurring chicken ovarian tumors pathologically resemble and behave similar to human ovarian tumors. However, to date, the use of the hen as a preclinical model has been directed towards prevention strategies versus targeted therapies for the disease. In this study, we designed and tested a chicken TAG72-CAR construct in an epHIV7 lentivirus backbone under the EF1a promoter that contains all the major CAR domains specific to chickens for the transduction of chicken peripheral blood mononuclear cells. After optimizing the production of CAR T cells, we further characterized their effector function by investigating various cell surface markers, targeted-killing capabilities, and activation/exhaustion marker expression. We observed a greater killing capacity within a 24-hour exposure period to ovarian cancer cells, such as human immortalized ovarian tumor cells (OVCAR3), displaying the target antigen compared to the later time exposures of 48 hours and/or 72 hours. The activation and exhaustion surface markers analyzed throughout the experiments support the high killing capacities earlier in exposure, with elevated activation and exhaustion occurring at later time points. In this study, chicken TAG72-CAR T cells were successfully generated, characterized, and tested as a therapeutic approach for treating OvCa in the hen, and will be further used to evaluate their in vivo efficacy in the hen model. The ability to test therapeutic strategies in an in vivo model that biologically and physiologically parallels the disease in women allows for the improvement of OvCa diagnosis and prognosis. Citation Format: Emily L. Cauble, Eric Lee, Cody Cullen, Saul J. Priceman, Lorna R. Rodriguez, Lindsey S. Treviño. Engineering TAG72-CAR T cells as a therapeutic strategy in the hen - a spontaneous, preclinical model for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1792.
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