Clinical Relevance of Matrix Metalloproteases and their Inhibitors in Breast Cancer

González

Fraile

et al. 2019

Cancers

Although the mechanisms underlying the genesis and progression of breast cancer are better understood than ever, it is still the most frequent malignant tumor in women and one of the leading causes of cancer death. Therefore, we need to establish new approaches that lead us to better understand the prognosis of this heterogeneous systemic disease and to propose new therapeutic strategies. Cancer is not only a malignant transformation of the epithelial cells merely based on their autonomous or acquired proliferative capacity. Today, data support the concept of cancer as an ecosystem based on a cellular sociology, with diverse components and complex interactions between them. Among the different cell types that make up the stroma, which have a relevant role in the dynamics of tumor/stromal cell interactions, the main ones are cancer associated fibroblasts, endothelial cells, immune cells and mesenchymal stromal cells. Several factors expressed by the stroma of breast carcinomas are associated with the development of metastasis, such as matrix metalloproteases, their tissular inhibitors or some of their regulators like integrins, cytokines or toll-like receptors. Based on the expression of these factors, two types of breast cancer stroma can be proposed with significantly different influence on the prognosis of patients. In addition, there is evidence about the existence of bi-directional signals between cancer cells and tumor stroma cells with prognostic implications, suggesting new therapeutic strategies in breast cancer.

Section: Stroma Phenotype Associated With Tumor Metastasismentioning

confidence: 99%

Breast Cancer Tumor Stroma: Cellular Components, Phenotypic Heterogeneity, Intercellular Communication, Prognostic Implications and Therapeutic Opportunities

González

Fraile

et al. 2019

Cancers

“…Our results are in accordance with previous reports showing that MMPs are overexpressed in PCa in comparison with prostate benign tissues [ 21 , 28 ]. MMPs have a key role in cancer progression by positively affecting several basic processes, such as invasion metastasis, angiogenesis, or proliferation (for review: [ 14 , 29 ]). Consequently, MMP expression was also associated with tumor progression and poor prognostic in PCa [ 21 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Matrix metalloproteases (MMPs) have reached an extraordinary interest in cancer research due to their role in tumor invasion and metastasis, by degrading basal membrane and extracellular matrix degradation [ 13 ]. In addition, MMPs are able to impact other basic processes of tumor progression, such as inhibiting apoptosis, stimulating proliferation, or regulating cancer/related angiogenesis (for review: [ 14 ]). On the other hand, it is assumed that tissue inhibitors of MMPs (TIMPs) are multifactorial proteins also involved in the induction of cell proliferation and the inhibition of apoptosis [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Matrix Metalloproteases by Artificial Intelligence Techniques in Negative Biopsies as New Diagnostic Strategy in Prostate Cancer

Medina

González

et al. 2023

IJMS

Usually, after an abnormal level of serum prostate-specific antigen (PSA) or digital rectal exam, men undergo a prostate needle biopsy. However, the traditional sextant technique misses 15–46% of cancers. At present, there are problems regarding disease diagnosis/prognosis, especially in patients’ classification, because the information to be handled is complex and challenging to process. Matrix metalloproteases (MMPs) have high expression by prostate cancer (PCa) compared with benign prostate tissues. To assess the possible contribution to the diagnosis of PCa, we evaluated the expression of several MMPs in prostate tissues before and after PCa diagnosis using machine learning, classifiers, and supervised algorithms. A retrospective study was conducted on 29 patients diagnosed with PCa with previous benign needle biopsies, 45 patients with benign prostatic hyperplasia (BHP), and 18 patients with high-grade prostatic intraepithelial neoplasia (HGPIN). An immunohistochemical study was performed on tissue samples from tumor and non-tumor areas using specific antibodies against MMP -2, 9, 11, and 13, and the tissue inhibitor of MMPs -3 (TIMP-3), and the protein expression by different cell types was analyzed to which several automatic learning techniques have been applied. Compared with BHP or HGPIN specimens, epithelial cells (ECs) and fibroblasts from benign prostate biopsies before the diagnosis of PCa showed a significantly higher expression of MMPs and TIMP-3. Machine learning techniques provide a differentiable classification between these patients, with greater than 95% accuracy, considering ECs, being slightly lower when considering fibroblasts. In addition, evolutionary changes were found in paired tissues from benign biopsy to prostatectomy specimens in the same patient. Thus, ECs from the tumor zone from prostatectomy showed higher expressions of MMPs and TIMP-3 compared to ECs of the corresponding zone from the benign biopsy. Similar differences were found for expressions of MMP-9 and TIMP-3, between fibroblasts from these zones. The classifiers have determined that patients with benign prostate biopsies before the diagnosis of PCa showed a high MMPs/TIMP-3 expression by ECs, so in the zone without future cancer development as in the zone with future tumor, compared with biopsy samples from patients with BPH or HGPIN. Expression of MMP -2, 9, 11, and 13, and TIMP-3 phenotypically define ECs associated with future tumor development. Also, the results suggest that MMPs/TIMPs expression in biopsy tissues may reflect evolutionary changes from prostate benign tissues to PCa. Thus, these findings in combination with other parameters might contribute to improving the suspicion of PCa diagnosis.

“…Matrix metalloproteases (MMPs) are zinc-dependent endopeptidases playing an important role in the degradation of the stromal connective tissue and basement membrane components, which are key elements during tumor invasion and metastasis. However, MMPs can participate in metastasis not only by remodeling the extracellular matrix, but also through their ability to cleave and activate growth factors, cell adhesion molecules, and cell surface receptor, resulting in an anti-apoptotic and/or pro-angiogenic effects [5].…”

Section: Introductionmentioning

confidence: 99%

MMP1 and MMP11 Expression in Peripheral Blood Mononuclear Cells upon Their Interaction with Breast Cancer Cells and Fibroblasts

Cid

Aguado

et al. 2020

IJMS

Tumor-infiltrating immune cells phenotype is associated with tumor progression. However, little is known about the phenotype of the peripheral blood mononuclear cells (PBMC) from breast cancer patients. We investigated MMP1 and MMP11 expression in PBMC from breast cancer patients and we analyzed gene expression changes upon their interaction with cancer cells and cancer-associated fibroblasts (CAF). We measured the impact of PBMC on proinflammatory gene expression in breast cancer cells, normal fibroblast (NF), and CAF and the impact on proliferation and invasiveness capacity of breast cancer cells. Gene expression of MMP1 and MMP11 in PBMC from breast cancer patients (n = 54) and control (n = 28); expression of IL1A, IL6, IL17, IFNβ, and NFĸB in breast cancer cell lines (MCF-7 and MDA-MB-231); and, additionally, IL10 and MMP11 in CAF and NF were analyzed by qRT-PCR before and after co-culture. Our results show the existence of a subpopulation of breast cancer patients (25.9%) with very high levels of MMP11 gene expression in PBMC. Also, gene expression of MMP1 and MMP11 increases in PBMC after co-culture with breast cancer cell lines, NF or CAF. PBMC from healthy or breast cancer patients induce an increased proliferation rate on MCF-7 and an increased invasiveness capacity of MDA-MB-231. Finally, we show a differential expression profile of inflammatory genes in NF and CAF when co-cultured with control or breast cancer PBMC. We have observed that MMPs’ expression in PBMC is regulated by the microenvironment, while the expression of inflammatory genes in NF or CAF is differentially regulated by PBMC. These findings confirm the importance of the crosstalk between stromal cells and suggest that PBMC would play a role in promoting aggressive tumor behavior.