Collagen and Discoidin Domain Receptor 1 Partnership: A Multifaceted Role in the Regulation of Breast Carcinoma Cell Phenotype

Type I collagen, the major components of breast interstitial stroma, is able to regulate breast carcinoma cell behavior. Discoidin domain receptor 1 (DDR1) is a type I collagen receptor playing a key role in this process. In fact, collagen/DDR1 axis is able to trigger the downregulation of cell proliferation and the activation of BIK-mediated apoptosis pathway. The aim of this review is to discuss the role of two important factors that regulate these processes. The first factor is the level of DDR1 expression. DDR1 is highly expressed in epithelial-like breast carcinoma cells, but poorly in basal-like ones. Moreover, DDR1 undergoes cleavage by MT1-MMP, which is highly expressed in basal-like breast carcinoma cells. The second factor is type I collagen remodeling since DDR1 activation depends on its fibrillar organization. Collagen remodeling is involved in the regulation of cell proliferation and apoptosis through age- and proteolysis-related modifications.

Adipose Collagen Fragment: A Novel Adipose-Derived Extracellular Matrix Concentrate for Skin Filling

Background Skin filler is an option for treatment of skin aging and wrinkle formation; however, currently used fillers are limited by poor biocompatibility, rapid degradation, and possible hypersensitivity reactions. However, autologous adipose tissue-derived products have been recognized as promising options for skin rejuvenation. Objectives This study aimed to develop a novel adipose-derived product for skin filling. Methods Adipose collagen fragment (ACF) was prepared through pulverization, filtration, and centrifugation. The macrography, structure, types of collagen, and cell viability of ACF were evaluated by immunostaining, Western blotting, and cell culture assays. ACF, nanofat and phosphate-buffered saline (9 spots/side, 0.01 ml/spot) were intradermally injected in the dorsal skin of 36 female BALB/c nude mice; then, the skin filling capacity and collagen remodeling process were investigated. Twenty-one female patients with fine rhytides in the infraorbital areas were enrolled and received ACF treatment as clinical applications. Therapeutic effects and patients’ satisfaction scores were recorded. Results The ACF yield from 50 ml of Coleman fat was 4.91 ± 0.25 ml. ACF contained nonviable cells and high levels of collagen I, collagen IV, and laminin. Fibroblasts and procollagen significantly increased in ACF and ACF-treated dermis (p < 0.05). 85.7% of patients were satisfied with the therapy results, and no infections, injection site nodules, or other unwanted side effects were observed. Conclusions ACF significantly improved dermal thickness and collagen synthesis and may serve as a potential autologous skin filler.

Dynamics of fibril collagen remodeling by tumor cells using individual cell-based mathematical modeling

Many solid tumors are characterized by dense extracellular matrix (ECM) composed of various ECM fibril proteins that provide structural support and biological context for the residing cells. The growing tumor cell colonies are capable of remodeling the ECM structure in tumor immediate vicinity to form specific microenvironmental niches. The changes in fibril patterns of the collagen (one of the ECM proteins) surrounding the tumor can be visualized experimentally using both histology and fluorescent imaging. In particular, three diverse tumor associated collagen signatures (TACS) were identified and related to tumor behavior, such as benign growth or invasion. Here we will use an off-lattice hybrid agent-based model (MultiCell-LF) to identify the rules of cell-ECM interactions that guide the development of various patterns of alignment of the ECM fibrils.

Differential Incidence of Tongue Base Cancer in Male and Female HPV16-Transgenic Mice: Role of Female Sex Hormone Receptors

A growing proportion of oropharyngeal squamous cell carcinomas (OPSCC) are associated with infection by high-risk human papillomavirus (HPV). For reasons that remain largely unknown, HPV+OPSCC is significantly more common in men than in women. This study aims to determine the incidence of OPSCC in male and female HPV16-transgenic mice and to explore the role of female sex hormone receptors in the sexual predisposition for HPV+ OPSCC. The tongues of 30-weeks-old HPV16-transgenic male (n = 80) and female (n = 90) and matched wild-type male (n = 10) and female (n = 10) FVB/n mice were screened histologically for intraepithelial and invasive lesions in 2017 at the Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Portugal. Expression of estrogen receptors alpha (ERα) and beta (ERβ), progesterone receptors (PR) and matrix metalloproteinase 2 (MMP2) was studied immunohistochemically. Collagen remodeling was studied using picrosirius red. Female mice showed robust ERα and ERβ expression in intraepithelial and invasive lesions, which was accompanied by strong MMP2 expression and marked collagen remodeling. Male mice showed minimal ERα, ERβ and MMP2 expression and unaltered collagen patterns. These results confirm the association of HPV16 with tongue base cancer in both sexes. The higher cancer incidence in female versus male mice contrasts with data from OPSCC patients and is associated with enhanced ER expression via MMP2 upregulation.

Tetrathiomolybdate (TM)-associated copper depletion influences collagen remodeling and immune response in the pre-metastatic niche of breast cancer

Tetrathiomolybdate (TM) is a novel, copper-depleting compound associated with promising survival in a phase II study of patients with high-risk and triple-negative breast cancer. We sought to elucidate the mechanism of TM by exploring its effects on collagen processing and immune function in the tumor microenvironment (TME). Using an exploratory cohort, we identified markers of collagen processing (LOXL2, PRO-C3, C6M, and C1M) that differed between those with breast cancer versus controls. We measured these collagen biomarkers in TM-treated patients on the phase II study and detected evidence of decreased collagen cross-linking and increased degradation over formation in those without disease compared to those who experienced disease progression. Preclinical studies revealed decreased collagen deposition, lower levels of myeloid-derived suppressor cells, and higher CD4+ T-cell infiltration in TM-treated mice compared with controls. This study reveals novel mechanisms of TM targeting the TME and immune response with potential applications across cancer types.