Chemotherapy neurotoxicity is codependent on cancer
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ABSTRACT:
PROVIDER: PRJNA523238 | ENA |
REPOSITORIES: ENA
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Project description:Neurological disorders induced by chemotherapy, including pain and other debilitating sensory conditions correlate with alterations in diverse systemic, cellular, and molecular processes. Chemotherapeutic agents variously induce inflammatory responses, metabolic disorders and associated gene expression changes, all of which have the capacity to impact sensory function . Early evidence of independent effects by cancer alone on some of these same processes led us to hypothesize that neurological symptoms may emerge from cooperativity in the effects of chemotherapy and cancer. We tested this hypothesis in a rodent model of human colon cancer after a full course of human-scaled treatment with the commonly used chemotherapeutic agent oxaliplatin. Transcriptional profiling of dorsal root ganglia demonstrated that cancer and chemotherapy in combination produced changes that were unpredictable or undetectable from those observed with either alone. Unique combinatorial effects of chemotherapy and cancer were conserved as dysregulation of select ion-channel proteins and associated reduction in excitability of sensory neurons responsible for proprioception. Recognition of the non-additive interactions between chemotherapy and cancer may lead to the development of more effective strategies for the prevention and/or treatment of chronic neurological disorders commonly associated with cancer therapy. We used microarrays to detail the global programme of gene expression underlying neurologic dysfunction following chemotherapy treatment in animals bearing and not bearing cancer.
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Project description:Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.
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Project description:Cytotoxic chemotherapy is used to treat many thousands of patients across many cancer types annually. Recent studies have demonstrated that chemotherapy causes systemic response that can be exploited to promote cancer cell survival and dissemination, termed “chemotherapy-induced metastasis. However, there have been no studies investigating how chemotherapy alters the extracellular matrix of breast tumors, or if those changes might help to support metastatic dissemination. Here, we report the first characterization of the chemotherapy-treated breast cancer matrisome using the MMTV-PyMT transgenic mouse model of breast cancer. We identify distinct changes induced by different cytotoxic chemotherapies. In particular, we identify collagen IV as significantly associated with taxane-based chemotherapy treatment. Biological validation confirmed collagen IV as chemotherapy-associated and identified collagen IV-driven Src and FAK signaling as important mediators of invasion in the post-chemotherapy tumor microenvironment.
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