Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment

Kempen, Léon C van; Rhee, Jin Sae; Dehne, Kerstin; Lee, Jake; Edwards, Dylan R.; Coussens, Lisa M.

doi:10.1046/j.1432-0436.2002.700914.x

Cited by 74 publications

(73 citation statements)

References 33 publications

(72 reference statements)

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“…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. 34 MMP-7 contributes to the initiation of epithelial-to-mesenchymal transition by cleavage of E-cadherin.…”

Section: Discussionmentioning

confidence: 95%

“…34 MMP-7 contributes to the initiation of epithelial-to-mesenchymal transition by cleavage of E-cadherin. 33,35 In keratoacanthomas, MMP-7 protein was not generally expressed in keratinocytes. 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.…”

Section: Discussionmentioning

confidence: 99%

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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: 95%

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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“…This cellular microenvironment directly modulates tissue architecture, cell morphology, and cell fate (1,2), and the ECM-stromal cell interaction contributes to the neoplastic phenotype (3). The conversion of fibroblasts into myofibroblasts, as mediated by transforming growth factor-h1 (TGF-h1), is the most prominent stromal reaction in a large number of epithelial lesions (4 -6).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect

Sheffer

Leon

Pinthus

et al. 2007

Molecular Cancer Therapeutics

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Stromal myofibroblasts play an important role in tumor progression. The transition of fibroblasts to myofibroblasts is characterized by expression of smooth muscle genes and profuse synthesis of extracellular matrix proteins. We evaluated the efficacy of targeting fibroblast-to-myofibroblast transition with halofuginone on tumor progression in prostate cancer and Wilms' tumor xenografts. In both xenografts, low doses of halofuginone treatment, independent of the route of administration, resulted in a trend toward inhibition in tumor development. Moreover, halofuginone synergizes with low dose of docetaxel in prostate cancer and vincristine and dactinomycin in Wilms' tumor xenografts, resulting in significant reduction in tumor volume and weight comparable to the effect observed by high doses of the respective chemotherapies.

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“…Equal amounts of protein were diluted 1:1 in sample buffer and subjected to gelatin zymography as described previously. 1 …”

Section: Zymographymentioning

confidence: 99%

“…1 Along with increased production of extracellular proteolytic enzymes, [2][3][4] increased synthesis of type I collagen (Col(I)) and other matrix components by stromal cells has been documented in skin, mammary, colon and prostate carcinomas. [5][6][7][8][9] In squamous cell carcinomas of the skin, increased Col(I) synthesis by stromal fibroblasts 9 is also accompanied by enhanced remodeling due to increased activity of matrix proteinases.…”

mentioning

confidence: 99%

Type I collagen expression contributes to angiogenesis and the development of deeply invasive cutaneous melanoma

Kempen

Rijntjes

Mamor-Cornelissen

et al. 2007

Intl Journal of Cancer

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Tumors are complex tissues composed of neoplastic cells, soluble and insoluble matrix components and stromal cells. Here we report that in melanoma, turn-over of type I collagen (Col(I)), the predominant matrix protein in dermal stroma affects melanoma progression. Fibroblasts juxtaposed to melanoma cell nests within the papillary dermis display high levels of Col(I) mRNA expression. These nests are enveloped by collagen fibers. In contrast, melanoma-associated fibroblasts within the reticular dermis express Col(I) mRNA at a level that is comparable to its expression in uninvolved dermis and reduced amount of collagen protein can be observed. To determine the significance of Col(I) expression in melanoma, we pharmacologically inhibited its transcription in a porcine cutaneous melanoma model by oral administration of halofuginone. When administered before melanoma development, it reduced melanoma incidence and diminished the transition from microinvasive toward deeply invasive growth by limiting the development of a tumor vasculature. Whereas invasive melanoma growth has been correlated with increased blood vessel density previously, our data for the first time demonstrate that the proangiogenic effect of Col(I) expression by fibroblasts and vascular cells precedes the development of invasive melanomas in a de novo tumor model. ' 2007 Wiley-Liss, Inc.Key words: cutaneous melanoma; type I collagen; angiogenesis; MeLiM porcine melanoma model; halofuginone Tumor development and invasion into adjacent tissue is often accompanied by increased architectural disorder of the extracellular matrix (ECM) and cellular components especially at the invasive front of the neoplastic mass. 1 Along with increased production of extracellular proteolytic enzymes, 2-4 increased synthesis of type I collagen (Col(I)) and other matrix components by stromal cells has been documented in skin, mammary, colon and prostate carcinomas. [5][6][7][8][9] In squamous cell carcinomas of the skin, increased Col(I) synthesis by stromal fibroblasts 9 is also accompanied by enhanced remodeling due to increased activity of matrix proteinases. 10 In contrast, cutaneous melanoma, but with the exception of desmoplastic variants, is not associated with strong ECM remodeling, but is mainly characterized by pericellular proteolysis of Col(I) and elastin at the invasive front. 11 Expression of Col(I) and its contribution to melanoma development and progression have not been studied extensively.In skin, the fibril forming Col(I) is predominantly synthesized by fibroblasts and accounts for 80-90% of the collagenous proteins present in the dermis. 12 Col(I) fibers are composed of righthanded triple helical molecules of 1 Col(I)a2 and 2 Col(I)a1 chains and can be found in all dermal layers. 13 However, the architectural organization of Col(I) fibers is different in the papillary and reticular dermis. Whereas, Col(I) is found as a finely woven meshwork of fibers in the papillary dermis, a distinctive pattern of thick Col(I) bundles is found in reticular dermis.Th...

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Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment

Cited by 74 publications

References 33 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

Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect

Type I collagen expression contributes to angiogenesis and the development of deeply invasive cutaneous melanoma

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