Martínez-Pérez Julia, Lopez-Calderero Iker, Saez Carmen, Benavent Marta, Limon Maria L, Gonzalez-Exposito Reyes, Soldevilla Beatriz, Riesco-Martínez Maria Carmen, Salamanca Javier, Carnero Amancio, Garcia-Carbonero Rocio
Oncology Department, Hospital Universitario Virgen del Rocio, 41013 Seville, Spain; Instituto de Biomedicina de Sevilla (IBIS) (HUVR/Universidad de Sevilla/CSIC), Seville, Spain (Center Affiliated to the Red Tematica de Investigacion Cooperativa en Cancer [RTICC], Instituto Carlos III, Spanish Ministry of Science and Innovation), 41013 Seville, Spain.
Oncology Department, Hospital Universitario Virgen del Rocio, 41013 Seville, Spain.
Hum Pathol. 2017 Sep;67:119-125. doi: 10.1016/j.humpath.2017.05.025. Epub 2017 Jun 7.
Src belongs to a family of cytoplasmic tyrosine kinases that play a key role in tumor initiation and progression. Src activation has been associated with a more aggressive neoplastic phenotype and induces resistance to platinum agents in preclinical models. The aim of our study was to assess the prognostic and/or predictive value of Src activation in patients with stage II-III colon cancer. pSrc expression was assessed in paraffin-embedded tumor samples by immunohistochemistry (phospho-Y418, ab4816; Abcam). Cases were classified by staining intensity in 4 categories: no staining (0), weak (1+), moderate (2+), and intense (3+) staining. A total of 487 patients were evaluated (240 stage II, 247 stage III), of whom 298 (61%) had received adjuvant chemotherapy. Staining was absent in 78 (16%), weak in 262 (54%), moderate in 103 (21%), and intense in 44 (9%). High pSrc expression was significantly associated with decreased 5-year disease-free survival (39% versus 63% for patients with high versus low pSrc expression; hazard ratio, 0.56; P=.005) and overall survival (58% versus 74%; hazard ratio, 0.55; P=.02). Multivariate analysis confirmed pSrc expression as a significant prognostic factor both for disease-free survival and overall survival, independent of age, sex, tumor stage, bowel obstruction/perforation, or adjuvant chemotherapy. These findings illustrate the relevance of Src activation in colon cancer biology, conferring a poor prognosis to patients with early stage colon cancer regardless of adjuvant chemotherapy. Our findings may help improve prognostic stratification of patients for clinical decisions and open new avenues for potential pharmacologic manipulation that may eventually improve patients' outcomes.
Src属于细胞质酪氨酸激酶家族，在肿瘤的起始和进展中起关键作用。在临床前模型中，Src激活与更具侵袭性的肿瘤表型相关，并诱导对铂类药物的耐药性。我们研究的目的是评估Src激活在II - III期结肠癌患者中的预后和/或预测价值。通过免疫组织化学（磷酸化Y418，ab4816；Abcam）在石蜡包埋的肿瘤样本中评估pSrc表达。病例根据染色强度分为4类：无染色（0）、弱阳性（1 +）、中度阳性（2 +）和强阳性（3 +）染色。共评估了487例患者（240例II期，247例III期），其中298例（61%）接受了辅助化疗。78例（16%）无染色，262例（54%）弱阳性，103例（21%）中度阳性，44例（9%）强阳性。高pSrc表达与5年无病生存率显著降低相关（高pSrc表达患者为39%，低pSrc表达患者为63%；风险比，0.56；P = 0.005）和总生存率降低相关（58%对74%；风险比，0.55；P = 0.02）。多变量分析证实pSrc表达是无病生存率和总生存率的重要预后因素，独立于年龄、性别、肿瘤分期、肠梗阻/穿孔或辅助化疗。这些发现说明了Src激活在结肠癌生物学中的相关性，无论辅助化疗如何，都赋予早期结肠癌患者不良预后。我们的发现可能有助于改善患者的预后分层以用于临床决策，并为潜在的药物干预开辟新途径，最终可能改善患者的结局。
