Intratumoral collagen signatures predict clinical outcomes in feline mammary carcinoma

Abstract

Breast cancer is the most common cause of cancer-related deaths in women worldwide. Identification of reliable prognostic indicators and therapeutic targets is critical for improving patient outcome. Cancer in companion animals often strongly resembles human cancers and a comparative approach to identify prognostic markers can improve clinical care across species. Feline mammary tumors (FMT) serve as models for extremely aggressive triple negative breast cancer (TNBC) in humans, with high rates of local and distant recurrence after resection. Despite the aggressive clinical behavior of most FMT, current prognostic indicators are insufficient for accurately predicting outcome, similar to human patients. Given significant heterogeneity of mammary tumors, there has been a recent focus on identification of universal tumor-permissive stromal features that can predict biologic behavior and provide therapeutic targets to improve outcome. As in human and canine patients, collagen signatures appear to play a key role in directing mammary tumor behavior in feline patients. We find that patients bearing FMTs with denser collagen, as well as longer, thicker and straighter fibers and less identifiable tumor-stromal boundaries had poorer outcomes, independent of the clinical variables grade and surgical margins. Most importantly, including the collagen parameters increased the predictive power of the clinical model. Thus, our data suggest that similarities with respect to the stromal microenvironment between species may allow this model to predict outcome and develop novel therapeutic targets within the tumor stroma that would benefit both veterinary and human patients with aggressive mammary tumors.

Collagen molecular phenotypic switch between non-neoplastic and neoplastic canine mammary tissues

“…Spontaneously occurring canine mammary gland tumors (CMT) have been proposed to have advantages as a model of human breast cancer compared to murine models, particularly when examining the tumor stroma 9 – 11 . In fact, recent work supports similarities between prognostic collagen signatures of women and female dogs and cats 12 – 16 , indicating that a comparative oncology approach provides valuable insights into the role of collagen in directing clinical behavior of breast cancer of veterinary and human patients. Recent studies have shown that aberrant collagen cross-linking is in part responsible for stiffening tumor ECM that facilitates cancer progression and metastasis 1 , 17 , 18 .…”

“…In order to elucidate the molecular mechanisms driving tumorigenesis and metastatic potential as well as to develop therapeutic strategies for human breast cancer, a number of animal models such as mice 75 , rats 76 , 77 , cats 16 , 76 – 80 , and dogs 9 , 81 – 84 have been developed. Given the protracted timeline and staggering expense of cancer therapies (estimated US ~ $1.8 billion to bring a new therapeutic from target validation to market) 85 , compounded by the high rate of failure (59% of anti-neoplastic drugs entering Phase III clinical trials) 86 , 87 , it is imperative to examine toxicity and efficacy in preclinical trials using a model that most closely mimics breast cancer in women.…”

“…SHG images were taken and analyzed as previous described 12 , 16 . Briefly, a Leica SP8 confocal/multiphoton microscope (Leica Microsystems, Inc., Mannheim, Germany), was used to collect SHG (backward) signal.…”

VEGF Expression, Cellular Infiltration, and Intratumoral Collagen Levels after Electroporation-Based Treatment of Dogs with Cutaneous Squamous Cell Carcinoma

“…Aggressive carcinomas with shorter collagen fibers are present in female dogs with mammary tumors, which directly affects survival time [34]. This has also been observed in feline mammary tumors, wherein denser collagen, thicker and straighter fibers, and less identifiable tumor-stromal boundaries are associated with poorer outcomes, independent of clinical variables, thus increasing the predictive power of the clinical model [35].…”

Caracterização histomorfométrica e quantificação do colágeno tipo I e III do carcinoma mamário canino

“…Na medicina veterinária foram realizados poucos estudos para o melhor entendimento dessa interação entre o câncer de mama e a MEC em comparação aos estudos humanos (Case et al, 2017;Rosen et al, 2020).…”