Type III Collagen Directs Stromal Organization and Limits Metastasis in a Murine Model of Breast Cancer

Abstract

Breast cancer metastasis is the leading cause of cancer-related deaths in women worldwide. Collagen in the tumor microenvironment plays a crucial role in regulating tumor progression. We have shown that type III collagen (Col3), a component of tumor stroma, regulates myofibroblast differentiation and scar formation after cutaneous injury. During the course of these wound-healing studies, we noted that tumors developed at a higher frequency in Col3(+/-) mice compared to wild-type littermate controls. We, therefore, examined the effect of Col3 deficiency on tumor behavior, using the murine mammary carcinoma cell line 4T1. Notably, tumor volume and pulmonary metastatic burden after orthotopic injection of 4T1 cells were increased in Col3(+/-) mice compared to Col3(+/+) littermates. By using murine (4T1) and human (MDA-MB-231) breast cancer cells grown in Col3-poor and Col3-enriched microenvironments in vitro, we found that several major events of the metastatic process were suppressed by Col3, including adhesion, invasion, and migration. In addition, Col3 deficiency increased proliferation and decreased apoptosis of 4T1 cells both in vitro and in primary tumors in vivo. Mechanistically, Col3 suppresses the procarcinogenic microenvironment by regulating stromal organization, including density and alignment of fibrillar collagen and myofibroblasts. We propose that Col3 plays an important role in the tumor microenvironment by suppressing metastasis-promoting characteristics of the tumor-associated stroma.

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…Parity appears to increase collagen I deposition, but in an unorganized, uncrosslinked form, resulting in softer ECM and reduced risk of breast cancers [83]. Collagen III disrupts formation of dense, organized collagen I networks, resulting in softer ECM [94]. Loss of collagen III in mouse models is associated with tumor aggressiveness [94], though Col III is often observed to be overexpressed with increasing tumor grade [20,81,82,95].…”

“…Collagen III disrupts formation of dense, organized collagen I networks, resulting in softer ECM [94]. Loss of collagen III in mouse models is associated with tumor aggressiveness [94], though Col III is often observed to be overexpressed with increasing tumor grade [20,81,82,95]. Furthermore, reductions in collagen I density via TGFβ blockade likewise suggest that altering collagen network structure is a potential therapeutic target [96].…”

Comparison of Picrosirius Red Staining With Second Harmonic Generation Imaging for the Quantification of Clinically Relevant Collagen Fiber Features in Histopathology Samples

“…For example, established histology dyes (Masson's trichrome, Movat's pentachrome, picrosirius red [PSR]), [15][16][17][18] antibody detection, 19 polarization-based widefield imaging, 20 and second harmonic generation (SHG) imaging 21,22 have all been employed. Other imaging methods often associated with collagen imaging either do not offer the appropriate resolution for the assessment of collagen organization, such as optical coherence tomography, 23,24 or require non-routine sample preparation methods and offer limited field of view, such as transmission electron microscopy, 25 scanning electron microscopy, 26 and atomic force microscopy.…”

Classification of breast cancer stroma as a tool for prognosis

“…Recent evidence has shown that the tumour microenvironment plays a crucial role in regulating tumour progression by different mechanisms, such as suppression of the immune response and remodelling of the extracellular matrix (ECM). 2 In particular, the remodelling of collagen fibres at the tumour-stromal interface has been shown to adversely affect survival. 3 Stromal regions can be characterised according to their maturity.…”