Department of Dermatology and Venereology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.
Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), 50937 Cologne, Germany.
Int J Mol Sci. 2021 Nov 12;22(22):12276. doi: 10.3390/ijms222212276.
Maintaining a balanced state in remodeling the extracellular matrix is crucial for tissue homeostasis, and this process is altered during skin cancer progression. In melanoma, several proteolytic enzymes are expressed in a time and compartmentalized manner to support tumor progression by generating a permissive environment. One of these proteases is the matrix metalloproteinase 14 (MMP14). We could previously show that deletion of MMP14 in dermal fibroblasts results in the generation of a fibrotic-like skin in which melanoma growth is impaired. That was primarily due to collagen I accumulation due to lack of the collagenolytic activity of MMP14. However, as well as collagen I processing, MMP14 can also process several extracellular matrices. We investigated extracellular matrix alterations occurring in the MMP14-deleted fibroblasts that can contribute to the modulation of melanoma growth. The matrix deposited by cultured MMP14-deleted fibroblast displayed an antiproliferative and anti-migratory effect on melanoma cells in vitro. Analysis of the secreted and deposited-decellularized fibroblast's matrix identified a few altered proteins, among which the most significantly changed was collagen XIV. This collagen was increased because of post-translational events, while de novo synthesis was unchanged. Collagen XIV as a substrate was not pro-proliferative, pro-migratory, or adhesive, suggesting a negative regulatory role on melanoma cells. Consistent with that, increasing collagen XIV concentration in wild-type fibroblast-matrix led to reduced melanoma proliferation, migration, and adhesion. In support of its anti-tumor activity, enhanced accumulation of collagen XIV was detected in peritumoral areas of melanoma grown in mice with the fibroblast's deletion of MMP14. In advanced human melanoma samples, we detected reduced expression of collagen XIV compared to benign nevi, which showed a robust expression of this molecule around melanocytic nests. This study shows that loss of fibroblast-MMP14 affects melanoma growth through altering the peritumoral extracellular matrix (ECM) composition, with collagen XIV being a modulator of melanoma progression and a new proteolytic substrate to MMP14.
维持细胞外基质重塑的平衡状态对于组织稳态至关重要，而这一过程在皮肤癌进展过程中会发生改变。在黑色素瘤中，几种蛋白水解酶以时间和区室化的方式表达，通过生成允许肿瘤进展的环境来支持肿瘤的进展。这些蛋白酶之一是基质金属蛋白酶 14（MMP14）。我们之前曾表明，真皮成纤维细胞中 MMP14 的缺失会导致产生类似于纤维化的皮肤，从而阻碍黑色素瘤的生长。这主要是由于缺乏 MMP14 的胶原酶活性导致胶原 I 积累所致。然而，除了胶原 I 的加工外，MMP14 还可以加工几种细胞外基质。我们研究了 MMP14 缺失的成纤维细胞中发生的细胞外基质改变，这些改变可能有助于调节黑色素瘤的生长。体外培养的 MMP14 缺失的成纤维细胞沉积的基质对黑色素瘤细胞具有增殖抑制和迁移抑制作用。对分泌和沉积去细胞化的成纤维细胞基质的分析确定了一些发生改变的蛋白质，其中变化最显著的是胶原 XIV。由于翻译后事件，这种胶原增加，而从头合成不变。作为底物的胶原 XIV 不是增殖促进、迁移促进或黏附促进的，这表明其对黑色素瘤细胞具有负调节作用。与之一致的是，在野生型成纤维细胞基质中增加胶原 XIV 的浓度会导致黑色素瘤增殖、迁移和黏附减少。在 MMP14 缺失的成纤维细胞的小鼠模型中，在黑色素瘤的肿瘤周围区域检测到胶原 XIV 的积累增加，支持了其抗肿瘤活性。在晚期人类黑色素瘤样本中，与良性痣相比，检测到胶原 XIV 的表达降低，而该分子在黑素细胞巢周围的表达很强。这项研究表明，成纤维细胞-MMP14 的缺失通过改变肿瘤周围细胞外基质（ECM）组成来影响黑色素瘤的生长，而胶原 XIV 是黑色素瘤进展的调节剂和 MMP14 的新蛋白水解底物。
