Skin Extracellular Matrix Breakdown Following Paclitaxel Therapy in Patients with Chemotherapy-Induced Peripheral Neuropathy.
Skin Extracellular Matrix Breakdown Following Paclitaxel Therapy in Patients with Chemotherapy-Induced Peripheral Neuropathy.
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DOI：
10.3390/cancers15164191
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发表时间：
2023-08-21
期刊：
影响因子：
5.2
通讯作者：
Rieger S
中科院分区：
文献类型：
--
作者：
Staff NP;Hrstka SC;Dasari S;Capobianco E;Rieger S
化疗药物如紫杉醇（Taxol）在大多数患者中引起化疗诱导的周围神经病变（CIPN）。这种神经退化的情况的特征是疼痛，刺痛，温度敏感性和手脚麻木，即使在化疗治疗完成后也会持续存在。CIPN显著影响癌症患者的生活质量，如果出现严重症状，可能需要终止化疗。我们先前对斑马鱼和啮齿动物模型中紫杉醇诱导的周围神经病变机制的分析表明，CIPN的根本原因是细胞外基质的皮肤特异性分解。在这项研究中，我们的目的是研究紫杉醇治疗后，紫杉醇对乳腺癌患者皮肤中的CIPN的影响。我们对年龄在60 - 70岁之间的健康对照组和CIPN患者的远端腿部进行了皮肤穿刺活检。虽然CIPN患者和对照皮肤中存在类似的神经纤维密度，但皮肤活检的RNA测序显示与细胞外基质，细胞骨架，细胞周期调节和神经系统功能相关的基因表达发生了显着变化。此外，细胞外基质降解酶MMP-13的表达在CIPN患者的皮肤中升高，并且当用免疫染色评估时，在超微结构中存在胶原分解和基底膜变薄。这些发现表明细胞外基质重塑也可能有助于紫杉醇治疗后患者皮肤中的CIPN。化疗药物紫杉醇导致周围神经病变，这是一种剂量限制性副作用，在高达68%的癌症患者中。在这项研究中，我们研究了紫杉醇治疗对乳腺癌患者化疗诱导的周围神经病变（CIPN）的皮肤的影响，建立在斑马鱼和啮齿动物的先前研究结果的基础上。进行全面评估，包括神经系统检查和生活质量问卷调查，然后使用皮肤穿刺活检进行表皮内神经纤维（IENF）密度评估。此外，RNA测序，基质金属蛋白酶13（MMP-13）的免疫染色和透射电子显微镜提供了对该皮肤的分子和超微结构变化的见解。结果显示，尽管存在患者报告的CIPN症状，但对照组和CIPN患者之间的IENF密度无显著差异。然而，皮肤上的RNA测序和免疫染色显示MMP-13显著上调，已知MMP-13在紫杉醇治疗引起的CIPN中起关键作用。此外，参与细胞外基质，微管，细胞周期和神经系统的调节的各种基因显着和差异表达。皮肤的超微结构检查显示胶原和基底膜结构的变化。这些发现强调了在没有IENF密度变化的情况下CIPN的存在，并支持皮肤重塑作为CIPN的主要贡献者的作用。
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. 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.
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