Metalloproteinase-2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas

Fundyler, Olga; Khanna, Manish; Smoller, Bruce R.

doi:10.1038/modpathol.3800066

Cited by 35 publications

(44 citation statements)

References 32 publications

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“…30 We have recently shown that also MMP-26 is present in the pushing border of keratoacanthomas. 11 As the expression of MMP-2, -7, -8, and -13 has previously been detected in malignantly transformed human keratinocytes 10,17,31,32 in SCCs, but not in normal migrating keratinocytes, we chose them to begin with. Furthermore, in an epithelial carcinogenesis model of HPV16/MMP-9À/À mice, MMP-7 and MMP-13 are only seen in frank carcinoma 33 and in tumors both have been detected exclusively in malignantly transformed squamous cell carcinoma cells but not in premalignant lesions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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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-5c2 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-5c2 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 transformationspecific MMP-13 in keratoacanthomas suggests that they are not benign tumors but incomplete SCCs.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…Also up-regulated in cKO epidermis were other migration, wound-healing, and invasion-associated genes, including those encoding tenascin C, biglycan, K6, K16, matrix metalloproteinases (MMPs), and other basement membrane remodeling factors. Increased MMP-2 expression was notable, because it is a measure of metastatic aggressiveness for hSSCs (13).…”

Section: Resultsmentioning

confidence: 99%

Links between α-catenin, NF-κB, and squamous cell carcinoma in skin

Kobielak

Fuchs

2006

Proc. Natl. Acad. Sci. U.S.A.

118

136

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Cancers display a diverse set of cellular defects, which are thought to be elicited by multiple genetic mutations. In this study, we show that when a single adherens junction protein, ␣-catenin, is removed by conditional targeting, the entire skin epidermis systematically transforms to a hyperproliferative, invasive tissue replete with inflammation. Transcriptional profiling and biochemical analyses reveal that ␣-catenin ablation is accompanied by activation of NF-B and its proinflammatory target genes, along with genes involved in proliferation, wound healing, angiogenesis, and metastasis. Many of these alterations occur in vitro and in the embryo, and thus seem at least partly to be intrinsic to the loss of ␣-catenin. We show that reductions in ␣-catenin, activation of NF-B, and inflammation are common features of human squamous cell carcinomas of the skin.cancer ͉ inflammation ͉ E-cadherin A dherens junctions (AJs) are intercellular junctions prominent in normal epithelia and reduced in cancers. The prototypic transmembrane core of AJs is composed of Ecadherin, whose cytoplasmic domain binds ␤-catenin, which in turn binds ␣-catenin. ␣-Catenin then regulates actin dynamics to integrate AJs with the cytoskeleton and promote intercellular adhesion (1). Throughout development, epithelia also use AJs to coordinate and maintain an intricate balance between intercellular adhesion and growth control. The best-studied mechanism is through Wnt signaling, which stabilizes additional ␤-catenin to serve as a transcription cofactor for the Tcf͞Lef family of DNA binding proteins (2). Among the targets of Tcf͞Lef͞␤-catenin complexes are cell-cycle-regulated genes.Mutations in ␤-catenin, E-cadherin, and ␣-catenin genes have been found in some human cancers, and reduced E-cadherin and ␣-catenin are often prognostic markers of poor clinical outcome in squamous cell carcinomas (SCCs) (2, 3). It has been assumed that reductions in E-cadherin and ␣-catenin act by liberating ␤-catenin, freeing it to trigger Tcf͞Lef-mediated transcription and causing uncontrolled tumor growth (4, 5). Thus it is curious that in skin, 2 days after conditional ablation of ␣-catenin, the epidermis loses polarity and becomes hyperproliferative, yielding large masses that resemble SCC in situ, a precancerous state (6). By contrast, activating mutations in ␤-catenin typically result in benign hair tumors (pilomatricomas) rather than epidermal SCCs (7,8). Such findings cannot be explained by ␣-catenin acting simply as a tumor suppressor to sequester ␤-catenin.This conundrum prompted us to explore how loss of ␣-catenin elicits this phenotype. Here we report that ␣-catenin conditional knockout (cKO) epidermis systematically progresses from a hyperpoliferative adherent tissue to a dermal infiltrate of nonadherent, dysplastic cells. We have also unraveled a link between ␣-catenin and NF-B signaling that unexpectedly points to ␣-catenin at the nexus of additional pathways that go awry in cancers. ResultsProgression to Hyperproliferation and Invasion. K14-Cre͞␣-c...

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“…A special class of enzyme implicated in this process is MMP, which constitutes a large family, including collagenases, gelatinases, stromelysins, and membrane type-MMPs. The expression and gelatinolytic activity of MMP-9 and active MMP-2 are closely associated with cancer progression and metastasis in various types of cancer, such as cervical (46), renal (47), and ovarian (48) cancer as well as colon cancer (41). Considering the important role of gelatinases in cancer progression, the notion that an aberration of TIMP-1, a major inhibitor of gelatinases, could provide the driving force for cancer progression is likely to be pertinent.…”

Section: Discussionmentioning

confidence: 99%

Functional Proteomics Study Reveals That N-Acetylglucosaminyltransferase V Reinforces the Invasive/Metastatic Potential of Colon Cancer through Aberrant Glycosylation on Tissue Inhibitor of Metalloproteinase-

Kim

Hwang

Kang

et al. 2008

Molecular & Cellular Proteomics

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Cancer is a very complicated process, characterized by the uncontrolled, unbalanced overgrowth of malignant cells. The complexity of oncogenic processes and cancer progressions has demanded the discovery of biomarkers with a high sensitivity and specificity for diagnosis, prognosis, diseases monitoring, and therapeutic response prediction. Unfortunately, a discrete biomarker for colon cancer has yet to be discovered, although nearly 800,000 new colorectal cancer cases are thought to globally occur each year, which account for ϳ10% of all incident cancers, and the mortality from colorectal cancer is estimated at nearly 450,000 per year (1). MLI1 and MSH genes are associated with hereditary non-polyposis colon cancer (2), and the APC gene is associated with familial adenomatous polyposis (3), but those factors fail to account for an occurrence of wide range of colon cancer. Moreover, colon cancer is one of the epithelium-derived cancers in which the circumstantial factors govern over hereditary genetic factors. These require a clear marker that serves as tracer molecule for the efficacious treatment of colon cancer.Recent proteomics have focused on a dynamic alteration of post-translational modification of proteins, and many lines of evidence indicate that changes in post-translational modification of proteins are closely associated with the pathogenic processes of cells. An aberrant glycosylation induced by Nacetylglucosaminyltransferase V (GnT-V), 1 is a representative example of such protein modification as is implicated in tumor progression. An increase in ␤1,6-branching on N-linked glycans is associated with metastatic potential of cancer cells (4). Several target molecules for GnT-V were proposed to be involved in cancer progressions, including matriptase (5), ␤ 1 integrin (6), and N-cadherin (7). However, those proteins are membrane-bound proteins and were not demonstrated to be aberrantly glycosylated in sera or tissues of cancer patients. Recent work stresses the discrete roles of the microenviron-

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Metalloproteinase-2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas

Cited by 35 publications

References 32 publications

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

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

Links between α-catenin, NF-κB, and squamous cell carcinoma in skin

Functional Proteomics Study Reveals That N-Acetylglucosaminyltransferase V Reinforces the Invasive/Metastatic Potential of Colon Cancer through Aberrant Glycosylation on Tissue Inhibitor of Metalloproteinase-

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