Abstract
Although many tumors regress in response to neoadjuvant chemotherapy, residual tumor cells are detected in most cancer patients post-treatment. These residual tumor cells are thought to remain dormant for years before resuming growth, resulting in tumor recurrence. Considering that recurrent tumors are most often responsible for patient mortality, there exists an urgent need to study signaling pathways that drive tumor dormancy/recurrence. We have developed an in vitro model of tumor dormancy/recurrence. Short-term exposure of tumor cells (breast or prostate) to chemotherapy at clinically relevant doses enriches for a dormant tumor cell population. Several days after removing chemotherapy, dormant tumor cells regain proliferative ability and establish colonies, resembling tumor recurrence. Tumor cells from “recurrent” colonies exhibit increased chemotherapy resistance, similar to the therapy resistance of recurrent tumors in cancer patients. Previous studies using long-term chemotherapy selection models identified acquired mutations that drive tumor resistance. In contrast, our short term chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that can resume growth after drug removal. Studying unique signaling pathways in dormant tumor cells enriched by short-term chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence.
Highlights
Despite the apparent efficacy of chemotherapy in ‘‘shrinking’’ primary tumors, chemotherapy-resistant tumor cells are thought to contribute to future tumor recurrence, the leading cause of patient mortality [1]
Using short term chemotherapy treatment to enrich for drugresistant tumor cells, we have developed an in vitro model of tumor recurrence
Several studies indicate that drug-resistant, slow-cycling tumor cells are represented at low frequency in human tumors, and are therapy resistant [5,6]
Summary
Despite the apparent efficacy of chemotherapy in ‘‘shrinking’’ primary tumors, chemotherapy-resistant tumor cells are thought to contribute to future tumor recurrence, the leading cause of patient mortality [1]. The identification of proteins that confer chemotherapy resistance has historically relied on studies of signaling pathways supported by tumor cells subjected to long-term, high dose drug selection [2,3]. These long-term selection models select for mutations/epigenetic modifications that result in acquired expression/activity of proteins involved in therapy resistance. Other models propose that tumors are heterogeneous, consisting of therapy-sensitive and therapy-resistant tumor cell subpopulations [5,6,7,8,9,10]. Such studies will be critical to defining logical therapeutic targets for preventing tumor recurrence
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