Abstract 4946: Host tissue stiffness regulates chemotherapy-induced cancer cell dormancy

Abstract

Abstract This study investigates how the tumor microenvironment, namely host tissue stiffness, affects the propensity of disseminated tumor cells to become dormant at secondary sites. Approximately 90% of cancer-related deaths result from metastasis. In breast cancer, disseminated cancer cells cannot be detected at the time of diagnosis of the primary tumor because they form “dormant” micrometastases that are not clinically detectable. Thus, metastases in secondary sites such as the lungs, bone marrow, liver and brain are usually discovered months or years after the initial diagnosis and/or treatment of the primary tumor. A 2D polyacrylamide gel-based tissue culture model was used to investigate the effects of host tissue stiffness on the proliferative behavior of breast cancer cells. To assess the dormant phenotype, Ki67 and RNA staining were used to quantify proliferation and RNA content, respectively. Additionally, changes in levels of cell-cycle regulators were determined by quantitative RT-PCR. Dormant cells have decreased levels of transcription and proliferation. We found that both tamoxifen and 5-fluorouracil induce dormancy in estrogen receptor-positive breast cancer cells cultured on soft and stiff substrata. After repeated rounds of 5-fluorouracil treatment and recovery, cells cultured on soft substratum, mechanical properties of which represent common metastatic sites, had a higher tendency to recover. This suggests that cell growth at secondary sites favors a soft microenvironment, characteristic of organs where breast cancer metastases often become clinically overt. Dormant cancer cells, or minimal residual disease, cannot be detected with current diagnostic tools and cannot be targeted by conventional therapies. Therefore, current clinical practices rely on estimating the probability of recurrence from various prognostic factors including the grade and the stage of the disease. Elucidating the mechanisms that regulate the switch from dormancy to proliferation at metastatic sites will pave the way for new treatments to control this incurable disease. Citation Format: Alisya Anlas, Celeste M. Nelson. Host tissue stiffness regulates chemotherapy-induced cancer cell dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4946. doi:10.1158/1538-7445.AM2017-4946