Journal Article

Identification of prognostic collagen signatures and potential therapeutic stromal targets in canine mammary gland carcinoma

Case, Ashley, Durham, Amy C., Salah, Pascale, Brisson, Becky K., Rosen, Suzanne, Ruthel, Gordon, Brown, Dorothy C., Buza, Elizabeth, Volk, Susan W., Sørenmo, Karin U., Monslow, James, Kristiansen, Veronica, Gillem, Julie, Veluvolu, Sridhar, Puré, Ellen

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adjuvant chemotherapy / Animals / Bioindicators / Biology and Life Sciences / Biomarkers / Biomarkers, Tumor - metabolism / Biopsy / Breast cancer / Cancer / Cancer metastasis / Carcinoma / Collagen / Collagen - metabolism / Collagen - ultrastructure / Density / Development and progression / Disease Progression / Dogs / Extracellular Matrix - metabolism / Extracellular Matrix - ultrastructure / Female / Identification methods / Lymphatic Metastasis / Lymphatic system / Mammary gland / Mammary Glands, Animal - diagnostic imaging / Mammary Glands, Animal - pathology / Mammary Glands, Animal - surgery / Mammary Neoplasms, Animal - diagnostic imaging / Mammary Neoplasms, Animal - mortality / Mammary Neoplasms, Animal - pathology / Mammary Neoplasms, Animal - surgery / Mathematical models / Medical prognosis / Medicine and Health Sciences / Metastases / Metastasis / Microscopy, Fluorescence, Multiphoton / Neoplasm Grading / Neoplasm Staging / Parameter identification / Patients / Prognosis / Quality / Risk / Second harmonic generation / Signatures / Straightness / Survival / Survival Analysis / Therapy / Translation / Treatment Outcome / Tumor Microenvironment / Tumor removal / Tumors / Veterinary colleges / Veterinary medicine / Womens health