MMP14 in Sarcoma: A Regulator of Tumor Microenvironment Communication in Connective Tissues - PubMed (original) (raw)
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MMP14 in Sarcoma: A Regulator of Tumor Microenvironment Communication in Connective Tissues
Jordi Gonzalez-Molina et al. Cells. 2019.
Abstract
Sarcomas are deadly malignant tumors of mesenchymal origin occurring at all ages. The expression and function of the membrane-type matrix metalloproteinase MMP14 is closely related to the mesenchymal cell phenotype, and it is highly expressed in most sarcomas. MMP14 regulates the activity of multiple extracellular and plasma membrane proteins, influencing cell-cell and cell-extracellular matrix (ECM) communication. This regulation mediates processes such as ECM degradation and remodeling, cell invasion, and cancer metastasis. Thus, a comprehensive understanding of the biology of MMP14 in sarcomas will shed light on the mechanisms controlling the key processes in these diseases. Here, we provide an overview of the function and regulation of MMP14 and we discuss their relationship with clinical and pre-clinical MMP14 data in both adult and childhood sarcomas.
Keywords: MMP14; mesenchymal phenotype; metastasis; sarcoma; tumor microenvironment.
Conflict of interest statement
The authors declare no conflict of interest. The funders had no role in the design of the study, in the writing of the manuscript, or in the decision to publish the results.
Figures
Figure 1
MMP14 expression in cancer. (A): Examples of MMP14 protein expression (in brown) in sarcoma (uterine sarcoma) and carcinoma (prostate carcinoma) tumors. Whereas in epithelial cancers, either the tumor cells or adjacent cancer associated fibroblasts can express MMP14, the mesenchymal sarcoma cells themselves express the protease. Arrowheads indicate high MMP14-expressing regions. (B): MMP14 gene expression in various cancer types based on The Cancer Genome Atlas program (TCGA) (
) [28,29]. (C): MMP14 gene expression in various types of sarcoma (
) [30].
Figure 2
MMP14 is regulated at the transcriptional level by multiple activators (highlighted in green) and a repressor (in red). DNA methylation (M) in the promoter region also regulates the transcription of the MMP14 gene. At the first post-transcriptional level, various microRNAs (in yellow), including several microRNAs with reported activities in various types of sarcoma, have been shown to target and thus reduce the translation of MMP14 mRNA.
Figure 3
The plasma membrane expression of MMP14 is highly regulated. After translation, MMP14 is an inactive zymogen containing an inhibitory pro-domain that is cleaved in the Trans-Golgi Network by proprotein convertases (i.e., furin). Thereafter, MMP14 is transported to invadopodia, actin-rich protrusions with high matrix degradation capabilities, through microtubules. Internalization of MMP14 occurs via clathrin-, flotillin-, and/or caveolin 1-dependent endocytosis. The internalized MMP14 is then stored in late and recycling endosomes, where it can be re-directed to the plasma membrane, or degraded in lysosomes.
Figure 4
The structure and mechanical properties of the ECM, as well as MMP14 activity can all affect the mode of 3D cell migration. (A): Mesenchymal cells embedded in a dense 3D collagen matrix migrate collectively due to the formation of microtracks initiated by the MMP14-dependent collagenolysis first induced by leader cells. (B): In mesenchymal cells migrating in matrices with small pores (confined environment), MMP14-rich endosomes are polarized in front of the nucleus to direct the matrix degradation pericellularly towards the direction of the migration enabling the formation of pores wider than the cell nucleus. This endosome polarization depends on the LINC complex and the positioning of the centrosome ahead of the nucleus. (C): The type of 3D cell migration depends on characteristics of the matrix such as pore size and its elasticity and plasticity but also depend on cellular features such as the activity of MMP14, and that of the Rho GTPases Rac1, cdc42 impacting on the formation of invadopodia and matrix degradation, and RhoA inducing myosin II-dependent contractility.
References
- Eisinger-Mathason T.S.K., Zhang M., Qiu Q., Skuli N., Nakazawa M.S., Karakasheva T., Mucaj V., Shay J.E.S., Stangenberg L., Sadri N., et al. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov. 2013;3:1190–1205. doi: 10.1158/2159-8290.CD-13-0118. - DOI - PMC - PubMed
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