Case Ashley, Brisson Becky K, Durham Amy C, Rosen Suzanne, Monslow James, Buza Elizabeth, Salah Pascale, Gillem Julie, Ruthel Gordon, Veluvolu Sridhar, Kristiansen Veronica, Puré Ellen, Brown Dorothy C, Sørenmo Karin U, Volk Susan W
Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
PLoS One. 2017 Jul 6;12(7):e0180448. doi: 10.1371/journal.pone.0180448. eCollection 2017.
Increasing evidence indicates that the tumor microenvironment plays a critical role in regulating the biologic behavior of breast cancer. In veterinary oncology, there is a need for improved prognostic markers to accurately identify dogs at risk for local and distant (metastatic) recurrence of mammary gland carcinoma and therefore would benefit from adjuvant therapy. Collagen density and fiber organization have been shown to regulate tumor progression in both mouse and human mammary tumors, with certain collagen signatures predicting poor outcomes in women with breast cancer. We hypothesized that collagen signatures in canine mammary tumor biopsies can serve as prognostic biomarkers and potential targets for treatment. We used second harmonic generation imaging to evaluate fibrillar collagen density, the presence of a tumor-stromal boundary, tumor associated collagen signatures (TACS) and individual collagen fiber characteristics (width, length and straightness) in grade I/II and grade III canine mammary tumors. Collagen density, as well as fiber width, length and straightness, were inversely correlated with patient overall survival time. Notably, grade III cases were less likely to have a tumor-stromal boundary and the lack of a boundary predicted poor outcome. Importantly, a lack of a defined tumor-stromal boundary and an increased collagen fiber width were associated with decreased survival even when tumor grade, patient stage, ovariohysterectomy status at the time of mammary tumor excision, and histologic evidence of lymphovascular invasion were considered in a multivariable model, indicating that these parameters could augment current methods to identify patients at high risk for local or metastatic progression/recurrence. Furthermore, these data, which identify for the first time, prognostic collagen biomarkers in naturally occurring mammary gland neoplasia in the dog, support the use of the dog as a translational model for tumor-stromal interactions in breast cancer.
越来越多的证据表明，肿瘤微环境在调节乳腺癌的生物学行为中起着关键作用。在兽医肿瘤学中，需要改进预后标志物，以准确识别有乳腺腺癌局部和远处（转移）复发风险的犬只，因此这些犬只将从辅助治疗中受益。胶原蛋白密度和纤维组织已被证明在小鼠和人类乳腺肿瘤中调节肿瘤进展，某些胶原蛋白特征预示着乳腺癌女性患者的不良预后。我们假设犬乳腺肿瘤活检中的胶原蛋白特征可作为预后生物标志物和潜在的治疗靶点。我们使用二次谐波产生成像来评估I/II级和III级犬乳腺肿瘤中的纤维状胶原蛋白密度、肿瘤-基质边界的存在、肿瘤相关胶原蛋白特征（TACS）以及单个胶原纤维特征（宽度、长度和直线度）。胶原蛋白密度以及纤维宽度、长度和直线度与患者总生存时间呈负相关。值得注意的是，III级病例更不容易有肿瘤-基质边界，而缺乏边界预示着不良预后。重要的是，即使在多变量模型中考虑了肿瘤分级、患者分期、乳腺肿瘤切除时的卵巢子宫切除术状态以及淋巴管浸润的组织学证据，缺乏明确的肿瘤-基质边界和胶原纤维宽度增加也与生存率降低相关，这表明这些参数可以增强当前识别局部或转移进展/复发高风险患者的方法。此外，这些首次在犬自然发生的乳腺肿瘤中鉴定出预后胶原蛋白生物标志物的数据，支持将犬作为乳腺癌肿瘤-基质相互作用的转化模型。
