细胞毒性化疗对乳腺癌患者分子年龄标志物的影响。
Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer.
机构信息
Affiliations of authors: Lineberger Comprehensive Cancer Center (HKS, AMD, JK, CT, JS, JGI, LAC, AD, B-BG, SA, NES, HBM), Department of Medicine (HKS, TAJ, GW, LAC, NES, HBM), Department of Genetics (JK, CT, NES), and Department of Biostatistics (JGI), University of North Carolina, Chapel Hill, NC; Department of Medicine, University of Virginia, Charlottesville, VA (PD); Department of Medical Oncology and Therapeutics Research, City of Hope Cancer Center, Duarte, CA (AH); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (KK, KLR).
出版信息
J Natl Cancer Inst. 2014 Apr;106(4):dju057. doi: 10.1093/jnci/dju057. Epub 2014 Mar 28.
BACKGROUND
Senescent cells, which express p16 (INK4a) , accumulate with aging and contribute to age-related pathology. To understand whether cytotoxic agents promote molecular aging, we measured expression of p16 (INK4a) and other senescence markers in breast cancer patients treated with adjuvant chemotherapy.
METHODS
Blood and clinical information were prospectively obtained from 33 women with stage I to III breast cancer at four time points: before anthracycline-based chemotherapy, immediately after anthracycline-based chemotherapy, 3 months after anthracycline-based chemotherapy, and 12 months after anthracycline-based chemotherapy. Expression of senescence markers p16 (INK4a) and ARF mRNA was determined using TaqMan quantitative reverse-transcription polymerase chain reaction in CD3(+) T lymphocytes, telomere length was determined by Southern analysis, and senescence-associated cytokines were determined by enzyme-linked immunosorbent assay. Findings were independently assessed in a cross-sectional cohort of 176 breast cancer survivors enrolled a median of 3.4 years after treatment; 39% previously received chemotherapy. All statistical tests were two-sided.
RESULTS
In prospectively analyzed patients, expression of p16 (INK4a) and ARF increased immediately after chemotherapy and remained elevated 12 months after treatment. Median increase in log2 p16 (INK4a) was 0.81 (interquartile range = 0.28-1.62; Wilcoxon signed-rank P < .001), or a 75% absolute increase in expression, equivalent to the increase observed over 14.7 years of chronological aging. ARF expression was comparably increased (P < .001). Increased expression of p16 (INK4a) and ARF was associated with dose-dense therapy and hematological toxicity. Expression of two senescence-associated cytokines (VEGFA and MCP1) was durably increased by adjuvant chemotherapy. Telomere length was not affected by chemotherapy. In a cross-sectional cohort, prior chemotherapy exposure was independently associated with a log2-increase in p16 (INK4a) expression of 0.57 (repeated measures model, P < .001), comparable with 10.4 years of chronological aging.
CONCLUSIONS
Adjuvant chemotherapy for breast cancer is gerontogenic, inducing cellular senescence in vivo, thereby accelerating molecular aging of hematopoietic tissues.
背景
衰老细胞表达 p16（INK4a），随着衰老而积累，并导致与年龄相关的病理学。为了了解细胞毒性药物是否促进分子衰老，我们测量了接受辅助化疗的乳腺癌患者中 p16（INK4a）和其他衰老标志物的表达。
方法
前瞻性地从 33 名 I 期至 III 期乳腺癌患者中获得血液和临床信息，在四个时间点：接受基于蒽环类药物的化疗前、基于蒽环类药物的化疗后立即、基于蒽环类药物的化疗后 3 个月和基于蒽环类药物的化疗后 12 个月。使用 TaqMan 定量逆转录聚合酶链反应在 CD3（+）T 淋巴细胞中测定衰老标志物 p16（INK4a）和 ARF mRNA 的表达，通过Southern 分析测定端粒长度，通过酶联免疫吸附试验测定衰老相关细胞因子。在治疗后中位数为 3.4 年的 176 名乳腺癌幸存者的横断面队列中独立评估了这些发现；39%的患者之前接受过化疗。所有统计检验均为双侧。
结果
在前瞻性分析的患者中，p16（INK4a）和 ARF 的表达在化疗后立即增加，并在治疗 12 个月后仍保持升高。p16（INK4a）的对数 2 增加的中位数为 0.81（四分位距=0.28-1.62；Wilcoxon 符号秩检验 P<.001），或表达增加 75%，相当于在 14.7 年的生理衰老中观察到的增加。ARF 的表达也有类似的增加（P<.001）。p16（INK4a）和 ARF 的表达增加与密集剂量治疗和血液学毒性有关。两种衰老相关细胞因子（VEGFA 和 MCP1）的表达被辅助化疗持久地增加。化疗对端粒长度没有影响。在横断面队列中，先前的化疗暴露与 p16（INK4a）表达的对数 2 增加 0.57 独立相关（重复测量模型，P<.001），与生理衰老 10.4 年相当。
结论
乳腺癌的辅助化疗是衰老的，在体内诱导细胞衰老，从而加速造血组织的分子衰老。
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