Cutaneous melanoma is an aggressive tumor with increasing incidence worldwide. Recent development of promising treatments based on immune checkpoints blockade in cancer immunotherapy or signal transduction inhibitors (B-Raf enzyme inhibitor and MEK inhibitor) requires identification of new biomarkers predictive of either prognosis and/or therapeutic response. Dynamic interaction between melanoma and normal host cells influences tumor progression; proteins regulating connections between melanoma cells and extracellular matrix facilitate tumor invasion and dissemination. We discuss the various functions of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in melanoma and their possible role as prognostic and/or predictive biomarkers. We also studied the correlation with regression of expression of several MMPs and TIMPs in melanoma; regressed and nonregressed components are in fact different tumor subclones; in some cases of melanoma with regression (with a specific morphology), the biologic aggressiveness of the tumor and implicitly the overall prognosis may be more favorable than that of melanoma without regression thus offering the possibility of a supplemental stratification of these patients beyond AJCC staging.
- matrix metalloproteinases
- tissue inhibitors of matrix metalloproteinases
Cutaneous melanoma represents one of the most important challenges in routine dermato-oncologic practice due to its increasing incidence worldwide. Its unfavorable prognosis with the increasing number of annual deaths and impressive death toll even in incipient melanoma cases  indicate that current stratification of melanoma patients staging system (American Joint Committee on Cancer—AJCC) based on certain morphologic parameters—Breslow thickness, ulceration, nodal and distant metastases—and a serum one—lactate dehydrogenase, is unsatisfactory for both tumor biologic behavior assessment and predictive value of the systemic treatment .
The most problematic melanoma patients fall in two main categories: patients with advanced disease (highly invasive thick lesions and/or regional lymph node metastasis) and patients with progressive disease despite incipient stage.
In case of patients with advanced disease, despite major efforts to improve treatment, no significant advance was obtained in the last two decades; lately, development of promising treatments based on immune checkpoints blockade in cancer immunotherapy (nivolumab and pembrolizumab as PD-1 inhibitors; ipilimumab as anti-CTLA4 monoclonal antibody) or signal transduction inhibitors such as B-Raf enzyme inhibitor (vemurafenib and dabrafenib) and MEK inhibitor (trametinib) has been attained [3–8]. Even so, most patients develop acquired resistance with subsequent evolution
The other type of patients, those with progressive disease despite incipient stage belongs to pT1 melanomas (less than 1 mm in maximum thickness, i.e., thin melanomas). Prognosis is highly favorable if the tumor is localized (without metastases, either local or distant), surgical resection with 1 cm healthy tissue being curative but there are few patients that eventually die due to disease progression. For this incipient stage, we must look to the dark side of the statistical data: 5 years survival rate for pT1 melanomas is 97.7% with 2.3% mortality due to disease; 10 years survival rate for pT1 melanomas is 95.1% with 4.9% mortality due to disease . Moreover, in case of patients with even thinner lesions (less than 0.75 mm), 10 years survival rate is 97% with a mortality rate due to disease of 3% [11, 12]. These data highlight the need for a supplementary stratification of patients with thin melanoma in “low risk” and “high risk” groups with subsequent more aggressive therapeutic approach for patients identified as “high risk” .
Identification of prognostic and/or predictive biomarkers is particularly difficult in cutaneous melanoma due to its complex biologic evolution, encumbered by myriad of different events caused by deregulations of several pathways . Dynamic interaction between melanoma and normal host cells influences tumor progression; proteins regulating connections between melanoma cells and extracellular matrix facilitate tumor invasion and dissemination . Cell adhesion molecules known to facilitate the metastatic potential of many cancers are also altered in melanoma when progressing from the non-invasive to the invasive growth phase and associate increased melanoma thickness and decreased survival [16, 17].
It becomes an imperious task that enzymes involved in degrading extracellular matrix should be investigated in relation with cancer invasion and metastases; these biomolecules belong to the metalloproteinases group that includes several classes of protease enzymes: matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTS). All of them are zinc-containing endopeptidases of metzincins family, some extracellular/soluble (most of MMPs and ADAMTS), the others membrane-bounded biomolecules (membrane-type MMPs (MT-MMPs) and ADAMs).
MMPs dysfunctions contribute to various diseases: degenerative diseases of the brain, atherosclerosis, aortic aneurysm, arthritis, and cirrhosis [25, 26]. In cancer, MMPs facilitate invasion and metastasis and participate as regulators of tumor cells proliferation and apoptosis; also, they intervene in tumor differentiation, tumor immune-resistance, and tumor angiogenesis [27, 28].
In tumor invasion, they mediate adhesion of tumor cells to extracellular matrix components and concomitant proteolysis of extracellular matrix, thus favoring migration of tumor cells into the areas of matrix degradation . Another important role of MMPs in cancer is represented by creation of a local environment able to host and provide specific conditions required by metastatic cells to survive in a distant organ—“metastatic niche” .
MMP-2 expression is correlated with prognosis being proposed as an independent prognostic factor . MMP-2 expression is variable in melanocytic tumors, according to their biologic aggressiveness. Thus, in benign melanocytic tumors (common nevocellular nevi), junctional nevi and melanoma, MMP-2 is present with differences in number according to cytonuclear and architectural features (more numerous cells as cell atypia and architectural disarray increase) [44–46]; MMP-2 was found over-expressed in lesional keratinocytes and enhanced by UVB-irradiation, but not found in melanocytic cells ; moreover, occurring of distant metastases is more frequent in melanomas with MMP-2 overexpression in primary tumor  but MMP-2 is not present in metastatic melanoma . Also, due to the relation between p-Akt and MMP2, MMP2 could be used as a predictive biomarker for vemurafenib resistance as vemurafenib-treated patients with overexpression of MMP-2 might be more prone to develop resistance [43, 48].
TIMPs directly interact with cell adhesion molecules or directly intervene on cytoskeletal components, processes that alter both intercellular adhesion and cell growth. In addition, cellular proliferation is modulated by TIMPs direct interference with components of extracellular matrix [83, 86].
TIMPs are involved in angiogenesis, mostly with anti-angiogenic effects due to the modulation of MMPs activity. However, TIMP2 and TIMP-3 have supplemental effects in inhibiting angiogenesis. TIMP-2 inhibits proliferation and migration of endothelial cells and (either by interacting with α3β receptor or by inducing the RECK expression which subsequent inhibition of MMP-2, MMP-9, MT1-MMP, ADAM10). TIMP-3 blocks VEGF-A mitogenic actions and regulates VEGFR2 expression [23, 83, 86, 87].
Tumor growth effects of TIMPs are also related to their intervention in apoptosis, either pro- or anti-apoptotic molecules. TIMP-1 and TIMP-2 have antiapoptotic activity modulating PI3-kinase and JNK pathways (unrelated to TIMP-1 inhibition of MMP functions) while TIMP-3 stabilizes Fas and TNF-cell receptor 1 (proapoptotic effects) [23, 83, 86, 88].
2. MMPs and TIMPs role in response to treatment and resistance to therapeutic agents in melanoma
In melanoma treatment with acute BRAF inhibition, it was reported that active MMP-2, MT1-MMP, and MMP-9 are decreased, but it did not modulate TIMP-2 or RECK. Using cell models, it was shown that resistance to vemurafenib induces significant changes in the tumor microenvironment mainly by MMP-2 upregulation, but not upon TIMP expression, MMP up-regulation corresponding to an increase in cell invasiveness . Another research group using experimental cell models by transfection of miR-21 and inducing over-expression in the melanoma cell lines WM1552c, WM793b, A375, and MEL 39 has shown that miR-21 decreases TIMP3 expression and enhances the invasiveness of melanoma cells. In an animal model, using 01B74 Athymic NCr-nu/nu mice, treatment with a miR-21 antagomir inhibited tumor growth and increased tumor expression of TIMP-3 .
3. MMPs and TIMPs expression in melanoma with regression
There are very few tumors that can present spontaneous regression up to the point of complete clinical and histopathologic vanishing. Melanoma is such a tumor, its disappearance reaching the point of impossibility of tumor cell identification even by immunohistochemical test; the indirect proof of previous existence of the tumor is represented by the presence of so-called tumor melanosis . There different types of regression in melanoma are described:
Regression is a phenomenon that occurs naturally relatively frequent in melanoma—up to 10–35% of cases; an even higher incidence was reported in thin melanomas—up to 60% of cases with a Breslow index of <0.75 mm [10, 92–94]. Despite these data, complete regression is reported in very few cases (mostly, as case reports and about 0.25% in large studies ); the real incidence of this phenomenon cannot be established since patients with completely regressed melanoma are not aware of the disease unless they develop distant metastasis. The biologic significance and prognosis of regression in melanoma is a matter of debate, various opinion being published [91, 96–105]. Mechanisms involved in occurring of regression in melanoma are yet to be deciphered; considering the importance of host response in this process, investigation of tumor microenvironment may offer some responses.
Study of MMPs and TIMPs expression in melanoma with regression was performed by our group by analyzing 93 melanomas (62 superficial spreading melanomas (SSM) and 31 nodular melanoma (NM)), 39 cases of SSM showing regression. Regression was present as both segmental and partial type, either pure form or combined (segmental regression (SR)—33.33%, partial regression (PR)—43.58%, and SR-PR in the same tumor—23.07%). Five MMPs and three TIMPs were analyzed (MMP-1, MMP-3, MMP-9, MMP-11, MMP-13, TIMP-1, TIMP-2, and TIMP-3) in both regressed and non-regressed areas of the tumors, the results being compared with those recorded in melanomas without regression (absence of regression—AR). A semiquantitative score with four levels based on the level of staining intensity, namely “absent” (−), “mild positive” (+), “moderate positive” (++), and “intense positive” (+++) was used to assess the immunohistochemical expression of each marker in either tumor or stromal cells.
Two types of results were obtained: (a) differences in MMPs and TIMPs expression between non-regressed component of melanoma with regression (NRC) and melanoma without regression (AR) and (b) differences in MMPs and TIMPs expression between regressed component (RC) and NRC in melanoma with regression .
3.1. Differences in MMPs and TIMPs expression in tumor cells between NRC and AR
MMP-1 was intense positive (+++) in all AR melanomas; also, most of the NRC were intense positive (+++) for MMP-1, only 15.84% of them being moderately positive (++) ( Figure 1a – c ). Despite the small percentage of less positive cases for MMP-1 in melanomas with regression, this feature was statistically significant.
Similar findings as in case of MMP-1 were present for MMP-11 ( Figure 1d – f ): all AR cases were intense positive, while 74.35% of NRCs were intense positive, the rest (25.65%) being moderate positive; also, the tendency of a diminished expression of MMP-11 in NRC than in AR cases was statistically significant.
MMP-2 ( Figure 2a – c ), MMP-3 ( Figure 2d – f ), MMP-7 ( Figure 2g – i ), MMP-9 ( Figure 2j – l ), and MMP-13 ( Figure 2m – o ) showed similar features of diminished expression in NRC than in AR but the data were not statistically significant; data for MMP-13 expression had a level of statistical significance of 0.07.
No significant differences for TIMP-1 ( Figure 3a – c ), TIMP-2 ( Figure 3d – f ), and TIMP-3 ( Figure 3g – i ) expression were recorded between NRC and AR tumor cells.
Our study identified an overall diminished expression of MMP-1, MMP-3, MMP-9, MMP-11, and MMP-13 in NRC comparing to AR as control; since most of these biomolecules have pro-tumor activities, it is possible to speculate that they favor a less aggressive biologic behavior melanoma with regression.
There were differences when the specific type of regression was considered. Expression of MMP-1 in NRC of tumors with SR (either SR or combined SR-PR) was statistically significant diminished comparing with both AR cases or with NRC in PR cases. No such differences were noted for other MMPs (MMP2, MMP3, MMP11, and MMP13). Expression of TIMP-1 and/or TIMP-2 in NRC of tumors with PR was statistically significant increased comparing with either NRC of SR cases (TIMP-1 P = 0.011; TIMP-2 P = 0.009) or with NRC of SR-PR cases and AR (P = 0.002 and 0.037, respectively). There was no difference in TIMP-3 expression in NRC and/or AR cases according to the type of regression.
3.2. Differences in MMPs and TIMPs expression between RC and NRC in melanoma with regression
The differences in MMPs and TIMPs expression were evaluated in the same tumor, both in tumoral and stromal cells. In case of tumors with SR, the expression was evaluated in stromal cells (fibroblasts) present in regressed area. In the other cases (PR tumors, SR-PR tumors, and AR tumors), most of the cases showed similar expression of each marker in tumor cells versus stromal fibroblast for each tumor compartment.
In all the cases, there was either similar expression of MMPs in tumor cells in both areas (NRC and RC) or slightly overexpression in NRC comparing with RC. MMP-3 was the biomolecule with the most numerous cases of overexpression (76.93% had MMP-3 overexpression in NRC than in RC), followed by MMP-2 and MMP-11 (58.97% each), MMP-13 (48.71%), and MMP-1 (30.76%). Tumor stromal fibroblasts were also slightly more intense positive in NRC than in RC or showed similar expression in both components.
Considering the specific type of regression, MMP2 was over-expressed tumor fibroblasts in NRC than in RC in PR cases comparing with SR ones (P = 0.023). Also, differences occurred in case of MMP-13 expression—all SR-PR cases had MMP-13 overexpression in NRC versus RC comparing with PR and SR cases (P = 0.003, respectively, P = 0.0003). No significant differences occurred in case of MMP-1, MMP-3, and MMP-11 expression.
TIMPs expression had more variability in NRC versus RC component both in tumoral and stromal cells; there were cases with overexpression, similar expression or diminished expression for each type of TIMP investigated. However, most of the cases (66.66% for TIMP-1, 61.53% for TIMP-2, and 64.10% for TIMP-3) had TIMP overexpression in NRC versus RC.
The type of regression did not influence TIMP-1 and TIMP-2 expression in NRC and RC. In case of TIMP-3, all SR melanomas had TIMP-3 overexpression in stromal tumor fibroblasts in NRC when compared with those in RC component (P = 0.007).
Cancer biology is a complex phenomenon, several mechanisms concurring to tumor progression and metastasis. The role of the tumor microenvironment and its regulation by both tumor neoplastic cells and host response was lately established, the identification of several stromal-related biomarkers offering some explanations for different biology behavior of tumors with otherwise similar origin and classical histopathologic appearance.
MMPs and TIMPs are potent molecules involved in tumor development, progression, and metastasis with either pro- and anti-tumor activity; their correlation with regression in melanoma shows: (a) regressed and nonregressed components are in fact different tumor subclones and (b) in some cases of melanoma with regression (with a specific morphology), the biologic aggressiveness of the tumor and implicitly the overall prognosis may be more favorable than that of melanoma without regression, thus offering the possibility of a supplemental stratification of these patients beyond AJCC staging. More studies are needed to establish comprehensive pathways as a gate for identification of new biomarkers for either diagnostic or therapeutic purposes.
This paper is partially supported by Executive Agency for Higher Education, Research, Development and Innovation (UEFISCDI) under the contract number PN-III-P4-ID-PCE-2016-0641 (Project No. 183/2017).
Conflict of interest
The authors declare no conflict of interests.
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