Wound Fluid as Regulator for Extracellular Matrix Remodeling and Recurrence in Inflammatory Breast Cancer

University Of Maryland Baltimore, Baltimore MD

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Abstract

It is well established that patients diagnosed with highly metastatic inflammatory breast cancer (IBC) have disease characterized by invasion of carcinoma cells into the lymphatic system, skin and axilla. High local recurrence rates on the chest wall and in the un-dissected regional nodes after neoadjuvant chemotherapy, mastectomy and radiation are well-documented and attributed to persistence of treatment resistant cells in the skin and residual lymphatics. Numerous genomic studies including recently presented next-generation sequencing demonstrate significant overlap with non-IBC cases suggesting non-genomic factors may influence the unique features of IBC. Together with studies showing that explicitly show non-tumor cells influence the IBC specific features of the tumor cells led us to investigate non-tumor factors to identify important targets in the microenvironment in IBC. Wound fluid obtained from post-surgical tumor cavities in non-IBC has recently been suggested to modulate biological activities in the tumor bed. In the present proposal, we aim to characterize cellular and proteomic components of the wound healing fluid collected during: 1) hemostasis/inflammatory; and 2) proliferating/tissue remodeling phases from non-IBC and IBC patients undergoing breast mastectomy. Wound fluid collected from benign breast lesions and mammoplasty will be used as control. First, we will collect the wound healing fluid to characterize epithelial and immunological cellular components using flow cytometric analysis. The proteomic profile of different phases of wound healing fluid will be assessed using cytokine antibody array. Since dynamic remodeling of the extracellular matrix (ECM) plays crucial role in cancer recurrence and dissemination, we will then develop 3D organotypic mammosphere (OMS) in-vitro culture model derived from patients? carcinoma tissues to test how wound healing fluid may regulate ECM remodeling. OMS will be seeded in media conditioned by wound fluid collected at different phases of the wound healing. After appropriate time of incubation, OMS will be subjected to RT² Profiler PCR Array that simultaneously detects the expression of 84 genes involved in ECM remodeling and cell adhesion. Finally, we plan to validate significant candidates identified from these steps in independent data at MD Anderson Cancer Center. Our study is critically important as the low survival rates of breast cancer in Egypt, especially among IBC patients, indicates a pressing need to develop collaborative research programs that can be of immediate assistance to patients. We anticipate that our findings will identify biological factors in the IBC wound fluid that may contribute to the dissemination of carcinoma cells all over the body and make the disease resistant to radiation and chemotherapy. The proposed research will be conducted primarily in Cairo, Egypt by faculty at Cairo University and Ain Shams University with collaborative engagement and support from colleagues at MD Anderson Cancer Center in Houston, Texas and University of Maryland School of Medicine in Baltimore, Maryland.