Matrix metalloproteinase-26 is present more frequently in squamous cell carcinomas of immunosuppressed compared with immunocompetent patients.

BACKGROUND: Skin cancers are the most frequent malignancies in organ transplant recipients (OTRs). Squamous cell carcinomas (SCCs) occur 65-250 times more frequently in OTRs and tend to be aggressive in behavior. Because matrix metalloproteinases (MMPs) have a central role in tumorigenesis and invasion, we investigated the epithelial and stromal MMP and tissue inhibitor of MMP (TIMP) expression profile in SCCs of immunosuppressed (IS) compared with immunocompetent (IC) patients to determine if differences could explain the more aggressive behavior of SCCs in OTRs. METHODS: Matched pairs from 20 SCCs of IS and IC patients were studied using immunohistochemistry for MMP-1, MMP-7, MMP-8, MMP-9, MMP-13 and MMP-26 and TIMP-1 and TIMP-3. RESULTS: Among all MMPs studied, only staining for MMP-26 was significantly more intense in cancer cells of the post-transplant group compared with the IC group (p = 0.01), whereas MMP-9 expression was more abundant in stromal macrophages surrounding SCCs of IC patients (p = 0.02). MMP-26 expression in cancer cells (p = 0.04) and that of MMP-9 in neutrophils (p = 0.005) were more abundant in SCCs of patients using cyclosporine. CONCLUSIONS: We conclude that MMP-26 and MMP-9 may contribute to the more aggressive behavior of SCCs in OTRs.

Differential expression of stromal MMP-1, MMP-9 and TIMP-1 in basal cell carcinomas of immunosuppressed patients and controls.

Matrix metalloproteinases (MMPs) have an important role in the initiation, growth, and invasion of malignant tumors. Basal cell cancer (BCC) is the most common human malignancy. The risk of BCC is 10-16 times higher among organ transplant recipients compared with the nontransplanted population. The aim of this study was to compare the expression of several MMPs and their tissue inhibitors (TIMPs) in BCCs from kidney transplant recipients and controls. Expression of MMPs-1, -7, -8, -9, -10, -13, -26, and TIMPs-1 and -3 was evaluated by immunohistochemistry in 25 samples of BCC of kidney transplant recipients and 25 matched controls representing superficial and nodular subtypes. No significant differences were detected in MMP expression of BCC tumor cells between immunocompetent and immunodeficient patients. However, MMPs-1 and -9 and TIMP-1 were expressed more frequently in stromal macrophages in the BCCs of immunocompetent patients. When tumor subtypes were compared irrespective of the patient group, more MMP-1-positive fibroblasts and MMP-9-positive neutrophils were detected in the superficial subtype, while stromal MMP-10 expression was more abundant in nodular tumors. Our results suggest that abundant peritumoral expression of TIMP-1 in non-immunocompromised patients limits ECM degradation permissive for cancer cell migration.

MMP-21 is upregulated at early stages of melanoma progression but disappears with more aggressive phenotype.

The expression of matrix metalloproteinases (MMPs) is frequently altered during malignant transformation. We examined the profile of three recently cloned MMPs, MMP-21, MMP-26, and MMP-28, in melanomas in vivo and in culture. Immunohistochemistry for MMPs-21, -26, -28, and -13 in melanoma specimens (27 nonmetastatic, 26 with nodal micrometastases, and 10 in situ melanomas) from 63 patients was performed. MMP-21 was expressed in melanoma cells in 29/53 cases, being more frequent in melanoma samples without micrometastases. Six out of ten in situ melanomas were positive, while five nevus samples were negative. MMP-26 and -28 were not generally expressed in melanoma cells. MMP-13 was detected in melanoma cells in 36/53 samples. MMP-21 was not found in sentinel nodes with metastases, while MMP-13 was seen in all of them. MMP-21 messenger RNA was variably expressed in all five melanoma cell lines investigated using reverse transcriptase-polymerase chain reaction. Our results suggest that expression of MMP-21 may serve as a marker of malignant transformation of melanocytes and does not associate with the presence of micrometastases.

Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas.

Keratoacanthomas are rapidly growing hyperproliferative skin tumors that may clinically or histologically be difficult to distinguish from well-differentiated squamous cell cancers (SCCs). UV light, trauma, and immune suppression represent their etiological factors. As matrix metalloproteinases (MMPs) are implicated at all stages of tumorigenesis, we investigated the expression profile of several cancer-related MMPs to find markers that would differentiate keratoacanthomas from SCCs and shed light to the pathobiology of keratoacanthoma. Samples from 31 keratoacanthomas and 15 grade I SCCs were studied using immunohistochemistry for MMP-2, -7, -8, -9, -10, -13, and -19 and p16 and laminin-5gamma2 chain. In situ hybridization for MMP-7, -10, and -13 was performed in a subset of tumors. Keratinocytes with atypia, presence of neovascularization, and composition of the inflammatory infiltrate were graded from hematoxylin-eosin stainings. MMP-7 was present in the epithelium of 4/31 keratoacanthomas and 9/15 SCCs, MMP-8 in 3/30 keratoacanthomas and 0/15 SCCs, but MMP-13 in 16/31 keratoacanthomas and 10/15 SCCs, and MMP-10 in 28/31 keratoacanthomas and all cancers. MMP-9 was detected in the epithelium in 5/31 keratoacanthomas and 8/15 SCCs, whereas MMP-2 was only present in fibroblasts in both tumors. MMP-19 was upregulated in proliferating epithelium of keratoacanthomas as was p16. Cytoplasmic laminin-5gamma2 was particularly abundant in keratinocytes at the pushing border of MMP-13-positive keratoacanthomas. We conclude that although some MMPs (MMP-10 and -13) are abundantly expressed in keratoacanthomas, the presence of MMP-7 and -9 in their epithelial pushing border is rare and should raise suspicion of SCC. Further, the loss of MMP-19 and p16 could aid in making the differential diagnosis between well-differentiated SCC and keratoacanthoma. Frequent expression of the transformation-specific MMP-13 in keratoacanthomas suggests that they are not benign tumors but incomplete SCCs.

Matrilysin-1 (MMP-7) and MMP-19 are expressed by Paget's cells in extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant neoplasm of apocrine gland bearing skin characterized by intraepidermal proliferation of adenocarcinoma cells. Tumor growth depends on the ability of tumor cells to migrate by proteolysis and on angiogenesis. The matrix metalloproteinase (MMP) enzymes have been implicated in both of these processes in other types of skin cancer. METHODS: The expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, and MMP-19 was analyzed by immuno- histochemistry and/or in situ hybridization in 27 EMPD and five mammary PD (MMPD) specimens. The distribution of laminin-5 (LN-5) and tenascin-C, two extracellular matrix proteins associated with tumor invasion, was studied by immunohistochemistry. RESULTS: MMP-7 (matrilysin-1) and MMP-19 were the most frequently expressed MMPs in Paget's cells. Overexpression of MMP-2, MMP-9, or MMP-13, which is seen in many cancers, was not evident in EMPD. LN-5 and tenascin-C positivity did not correlate with the level of invasion. MMP-7, MMP-13, and MMP-19 were detected abundantly in MMPD, while MMP-9 was absent. CONCLUSIONS: MMP expression did not generally associate with the level of invasion of EMPD. In three samples positive for MMP-7 and four samples positive for MMP-19, an underlying carcinoma was detected, suggesting the importance of these two MMPs as predictors of secondary EMPD or the putative origin of Paget's cells from the dermal adenocarcinoma cells of apocrine duct origin.