Skin Extracellular Matrix Breakdown Following Paclitaxel Therapy in Patients with Chemotherapy-Induced Peripheral Neuropathy

SIMPLE SUMMARY: Chemotherapy drugs like paclitaxel (Taxol) cause chemotherapy-induced peripheral neuropathy (CIPN) in the majority of patients. This condition of nerve degeneration is characterized by pain, tingling, temperature sensitivity, and numbness in the hands and feet and can persist even after chemotherapy treatment is completed. CIPN significantly affects the quality of life of cancer patients and can require the termination of chemotherapy if severe symptoms arise. Our prior analysis of the mechanisms of paclitaxel-induced peripheral neuropathy in zebrafish and rodent models revealed that the underlying cause of CIPN is a skin-specific breakdown of the extracellular matrix. In this study, we aimed to investigate the effects of paclitaxel in the skin of breast cancer patients with CIPN following paclitaxel therapy. We performed a skin punch biopsy on the distal leg of healthy control subjects and CIPN patients aged between 60 and 70 years. Although a similar nerve fiber density was present in the CIPN patient and control skin, the RNA sequencing of skin biopsies revealed significant gene expression changes in relation to the extracellular matrix, cytoskeleton, cell cycle regulation, and genes involved in the nervous system’s function. Furthermore, the expression of the extracellular matrix-degrading enzyme MMP-13 was elevated in the skin of CIPN patients, and also, when assessed with immunostaining, collagen breakdown, and basement membrane thinning were present at the ultrastructure. These findings indicate that extracellular matrix remodeling might also contribute to CIPN in patient skin following paclitaxel therapy. ABSTRACT: The chemotherapeutic agent paclitaxel causes peripheral neuropathy, a dose-limiting side effect, in up to 68% of cancer patients. In this study, we investigated the impact of paclitaxel therapy on the skin of breast cancer patients with chemotherapy-induced peripheral neuropathy (CIPN), building upon previous findings in zebrafish and rodents. Comprehensive assessments, including neurological examinations and quality of life questionnaires, were conducted, followed by intraepidermal nerve fiber (IENF) density evaluations using skin punch biopsies. Additionally, RNA sequencing, immunostaining for Matrix-Metalloproteinase 13 (MMP-13), and transmission electron microscopy provided insights into molecular and ultrastructural changes in this skin. The results showed no significant difference in IENF density between the control and CIPN patients despite the presence of patient-reported CIPN symptoms. Nevertheless, the RNA sequencing and immunostaining on the skin revealed significantly upregulated MMP-13, which is known to play a key role in CIPN caused by paclitaxel therapy. Additionally, various genes involved in the regulation of the extracellular matrix, microtubules, cell cycle, and nervous system were significantly and differentially expressed. An ultrastructural examination of the skin showed changes in collagen and basement membrane structures. These findings highlight the presence of CIPN in the absence of IENF density changes and support the role of skin remodeling as a major contributor to CIPN.