Human Collagenase-3 Is Expressed in Malignant Squamous Epithelium of the Skin

Abstract

Co-expression of several members of the matrix metalloproteinase (MMP) family is a characteristic of human carcinomas. To investigate the role of the recently cloned collagenase-3 (MMP-13) in epidermal tumors, we studied samples representing malignant (basal and squamous cell carcinoma, Paget's disease), pre-malignant (Bowen's disease, solar keratosis), and benign (keratoacanthoma, seborrheic keratosis, linear epidermal nevus) tumors. Basal cell carcinomas expressed collagenase-3 mRNA in focal areas of keratinized cells, the squamous differentiation of which was confirmed by positive immunostaining for involucrin. Apoptosis was observed in central parts of these foci. In squamous cell carcinomas, collagenase-3 expression was detected at the epithelial tumor front and less frequently in the surrounding stromal cells. Collagenase-3 mRNA co-localized with immunostaining for laminin-5, an adhesion molecule suggested to participate in the migration of tumor cells. The pre-malignant and benign tumors were mostly negative for collagenase-3. Stromelysin-1, a potential activator of latent collagenases, was frequently expressed by stromal cells surrounding the malignant tumors, and the two MMPs occasionally co-localized in keratotic foci. Our results demonstrate that in basal cell carcinomas, expression of collagenase-3 is associated with terminal differentiation of epithelial cells. Furthermore, the gene is activated during skin carcinogenesis, and we suggest a role for collagenase-3 in degradation of the extracellular matrix associated with malignant epithelial growth.

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

“…18,34 Several MMPs are known to process laminin-5g2 in vitro. 44 We have previously shown that in cutaneous SCCs, laminin5g2 is widely distributed along the invasive tumor front 26,41 and thus our current data show that, in general, staining for laminin-5 cannot help in differentiation between keratoacanthoma and SCC. In this work, we found colocalization of laminin-5 and MMP-10, a phenomenon previously reported in squamous and basal cell cancers.…”

“…However, MMP-13 expression, a specific marker for malignant transformation in keratinocytes, 36,37 was detected in the epithelium of half of the keratoacanthomas studied. Thus, staining for MMP-13 protein does not assist in distinguishing keratoacanthomas from grade I SCCs 26 and suggests that at least a subset of keratoacanthomas cannot be classified as benign. Low expression of another collagenase, MMP-8, was found in the epithelium in three of the keratoacanthoma samples, whereas neutrophils stained positively in the majority of specimens.…”

“…[23][24][25] In situ hybridization was performed on 5-mm sections as described in detail 26 to confirm immunohistochemical findings. Sections were hybridized with 35 S-labeled probes (3 Â 10 4 c.p.m./ml of hybridization buffer) at 501C for at least 18 h in a humidified chamber.…”

Serpin Peptidase Inhibitor Clade A Member 1 (SerpinA1) Is a Novel Biomarker for Progression of Cutaneous Squamous Cell Carcinoma

“…Particularly, among patients with a history and at high risk for skin cancer, regular screening is necessary to monitor the recurrence or persistence of the tumors. [1][2][3][4] At present, only a few specific biomarkers for cutaneous SCC have been identified, including STAT3, 44 E-cadherin, 45 and matrix metalloproteinases 13, 46 12, 47 and 7. 6,48 SerpinA1 has been previously suggested as a biomarker for the progression of insulinoma 49 and thyroid cancer.…”

Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells

“…However, the wide substrate specifity of MMP-13 suggests that it is also a powerful invasion tool for cancer cells. MMP-13 is one of the few MMPs primarily expressed by tumor cells in malignant tumors, such as breast carcinomas (Freije et al, 1994), squamous cell carcinomas (SCCs) of the head and neck (Airola et al, 1997;Johansson et al, 1997a), SCCs of the vulva (Johansson et al, 1999), and primary and metastatic melanomas (Airola et al, 1999;Nikkola et al, 2001). In SCCs of the head and neck and vulva, MMP-13 is expressed primarily by cancer cells at the invading edge of the tumor and the expression correlates with poor prognosis (Johansson et al, 1997a(Johansson et al, , 1999Cazorla et al, 1998).…”