Human keratinocyte growth factor activity on proliferation and differentiation of human keratinocytes: Differentiation response distinguishes KGF from EGF family

Marchese, Cinzia; Rubin, Jeffrey S.; Ron, Dina; Faggioni, Alberto; Torrisi, Maria Rosaria; Messina, Angela; Frati, Luigi; Aaronson, Stuart A.

doi:10.1002/jcp.1041440219

Cited by 214 publications

(149 citation statements)

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“…In fact, it has been known that KGF induces cell differentiation and suppresses cell proliferation in some cases. For example, KGF is known to promote the differentiation of keratinocytes derived from human neonatal foreskin 24,25 as well as human lung squamous cell carcinoma. 26 In human salivary gland tumors, loss of KGFR expression was observed in the process of malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 Moreover, KGF is known to have diverse effects, such as inhibition of apoptosis [21][22][23] and regulation of cell differentiation. [24][25][26] To help clarify these issues, it is desirable to localize KGF and KGFR at a cellular level in tissue sections of human breast cancer. Although KGF mRNA expression in ruminant mammary gland was previously detected by in situ hybridization using autoradiography, 27 there have been no reports on immunohistochemical analysis of KGF and KGFR expression in human breast cancer tissue.…”

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confidence: 99%

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Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer

Tamaru

Hishikawa

Ejima

et al. 2004

Laboratory Investigation

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Although estrogen is known to play a crucial role in the pathogenesis of breast cancer, the molecular mechanisms underlying the action of estrogen remain elusive. In the present study, we focused on keratinocyte growth factor (KGF) and its receptor (KGFR) in the pathogenesis of breast cancer, as a growth factor mediating estrogen action, since significant roles of KGF were demonstrated in various steroid hormone-dependent tissues. First, using paraffin-embedded specimens from 42 breast cancer patients, we examined expression patterns of KGF and KGFR by both immunohistochemistry using newly generated antibodies and nonradioactive in situ hybridization with T-T dimerized synthetic oligonucleotide probes. We next compared the results with the expression of estrogen receptor (ER) a and b, proliferative activity and apoptotic frequency (TUNEL staining). Also, the similar approaches were taken to analyze the expression and role of KGF in ERpositive (MCF7, ZR-75-1) and ER-negative (SK-BR-3, MDA-MB-231) human breast cancer cell lines in vitro. In the surgical specimens, KGF was expressed in cancer cells as well as stromal cells in 19/42 cases (45%), while KGFR was found in cancer cells in 24/42 cases (57%). The distribution of protein and mRNA in the analysis of both KGF and KGFR expression generally coincided. Moreover, KGF expression was closely associated with the expression of ER a, and the coexpression of KGF and KGFR significantly correlated with lower TUNEL index, but not with proliferative activity. In accordance with the in vivo findings, KGF expression was detected only in ER a-positive MCF7 and ZR-75-1 cells in vitro. And more importantly, we found the inhibitory effect of KGF upon the induction of apoptosis by anticancer drugs in MCF7 cells. Collectively, our results indicate that ER a may be involved in KGF expression, and that KGF may play antiapoptotic roles, rather than mitogenic, in human breast cancer. Keywords: apoptosis; breast cancer; estrogen receptor; immunohistochemistry; in situ hybridization; keratinocyte growth factor; TUNEL staining Breast cancer is the most frequent malignant tumor of women in the USA and European countries. In Japan, the frequency of breast cancer has rapidly increased during the last decade, and currently approximately 20 000 women develop breast cancer per year. However, our knowledge of the development and progression of breast cancer is still largely limited. The proliferation and differentiation of breast cancer cells are influenced by estrogen, 1-3 which exerts its action through binding to estrogen receptor (ER). Currently, ER is categorized into two subtypes, ER a and b, and both are believed to act as an active transcription factor, which binds to a specific DNA segment such as the estrogen responsive element (ERE) and AP-1 site, to regulate the expression of a variety of genes. 4,5 The majority of human breast cancer cells express both ER a and ER b. 6 While ER a is regarded as an indicator of

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer

Tamaru

Hishikawa

Ejima

et al. 2004

Laboratory Investigation

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“…However, other experimental approaches will be required to fully define the precise nature of KGF involvement in epithelial development. In this regard, earlier cell and organ culture studies have demonstrated that KGF is a paracrine mitogen for epithelial cells from a variety of different sources (Aaronson et al, 1991;Marchese et al, 1990;Pierce et al, 1994;Rubin et al, 1989;Ulich et al, 1994), as well as a morphogen in the ductal branching morphogenesis of the neonatal mouse seminal vesicle (Alarid et al, 1994) and the neonatal rat prostate (Sugimura et al, 1993). The extension of similar studies to other organ systems will provide a powerful approach in further elucidating the multiple roles of KGF during development.…”

Section: Discussionmentioning

confidence: 99%

Pattern of keratinocyte growth factor and keratinocyte growth factor receptor expression during mouse fetal development suggests a role in mediating morphogenetic mesenchymal‐epithelial interactions

Finch

Cunha

Rubin

et al. 1995

Developmental Dynamics

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Mesenchymal cells are required for the induction of epithelial development during mammalian organogenesis. Keratinocyte growth factor (KGF) is a mesenchymally derived mitogen with specific activity for epithelial cells, suggesting that it may play a role in mediating these interactions. To further evaluate this hypothesis, in situ hybridization was used to examine the spatial distribution of KGF and KGF receptor (KGFR) transcripts during organogenesis and limb formation in mouse embryos (days 14.5 through 16.5). To facilitate this aim, mouse KGF cDNA clones were isolated. There was extensive identity between the deduced mouse KGF protein sequence and that of its human and rat cognates, indicating that this gene has been highly conserved during mammalian evolution. In addition, mouse KGF protein was purified from fibroblasts and demonstrated to be structurally and functionally similar to human KGF protein. For organs within the integumental, respiratory, gastrointestinal, and urogenital systems, whose development is dependent upon mesenchymal‐epithelial interactions, KGF mRNA was detected in mesenchymal cells, while epithelial cells expressed transcripts for the KGFR. KGF and KGFR mRNA was also expressed in certain other tissues such as perichondrium, cartilage of developing bones, developing skeletal muscle, and visceral smooth muscle whose development is not regulated by mesenchymal‐epithelial interactions. KGF expression was also detected in tissues isolated from human embryos, suggesting similar functions for KGF in human development. Taken together, our results suggest that KGF plays an important role in mediating mesenchymal‐epithelial interactions during organogenesis, but may also have other developmental functions in tissues not governed by such interactions. ©1995 Wiley‐Liss, Inc.

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“…FGF-7 is a potent mitogen for keratinocytes and has also been shown to modulate differentiation (13,41). Primary cultures of human keratinocytes in basal medium were treated with 5 ng/ml FGF-7 in the presence of heparin or DS.…”

Section: Dermatan Sulfate Enhances the Proliferative Effect Of Fgf-7 mentioning

confidence: 99%

Dermatan Sulfate Binds and Potentiates Activity of Keratinocyte Growth Factor (FGF-7)

Trowbridge

Rudisill

Ron

et al. 2002

Journal of Biological Chemistry

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FGF-7 is induced after injury and induces the proliferation of keratinocytes. Like most members of the FGF family, the activity of FGF-7 is strongly influenced by binding to heparin, but this glycosaminoglycan is absent on keratinocyte cell surfaces and minimally present in the wound environment. In this investigation we compared the relative activity of heparan sulfate and chondroitin sulfate B (dermatan sulfate), glycosaminoglycans that are present in wounds. A lymphoid cell line (BaF/KGFR) containing the FGF-7 receptor (FGFR2 IIIb) was treated with FGF-7 and with various glycosaminoglycans. FGF-7 did not support cell proliferation in the absence of glycosaminoglycan or with addition of heparan sulfate or chondroitin sulfate A/C but did stimulate BaF/KGFR division in the presence of dermatan sulfate or highly sulfated low molecular weight fractions of dermatan. Dermatan sulfate also enabled FGF-7-dependent phosphorylation of mitogen-activated protein kinase and promoted binding of radiolabeled FGF-7 to FGFR2 IIIb. In addition, dermatan sulfate and FGF-7 stimulated growth of normal keratinocytes in culture. Thus, dermatan sulfate, the predominant glycosaminoglycan in skin, is the principle cofactor for FGF-7. Glycosaminoglycans (GAGs)1 and proteoglycans are emerging as key regulators of a variety of cellular behaviors involved in development, homeostasis, and disease. Heparin, heparan sulfate (HS), and hyaluronic acid are GAGs that have been studied extensively in relation to their roles in anticoagulation, growth factor signaling, and connective tissue support. Less well studied, dermatan sulfate (DS) is the predominant GAG expressed in the skin and is released at high concentrations during wound repair, making it a particularly interesting topic for evaluation in relation to growth factors active in wounds. Wound fluid-derived DS, as well as physiologic concentrations of commercially purified DS, has been shown to promote FGF-2 function (1). DS and DS proteoglycans also bind to and influence the activity of other heparin-and HS-binding proteins including hepatocyte growth factor/scatter factor (2), thrombin (3), heparin cofactor II (4, 5), fibronectin (6), platelet factor-4 (7), regulated on activation normal T cell expressed and secreted (RANTES) (8), and interferon-␥ (9, 10). Thus, although less well understood, DS-protein interactions are likely to be important events in control of several cellular behaviors.FGF-7 or keratinocyte growth factor is a polypeptide mitogen that belongs to the family of fibroblast growth factors. Whereas some FGF family members bind to multiple FGF receptors (FGFRs 1-4) (11) and stimulate proliferation in a variety of cell types, FGF-7 binds only to a splice variant of FGFR2 (FGFR2 IIIb) and is a highly specific paracrine growth factor for epithelial cells (12, 13). FGF-7 and its receptor are believed to be important for normal wound healing. The expression of FGF-7 and FGFR2 IIIb are induced in wounds (14, 15), and the application of FGF-7 to wounds has been shown to promote he...

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Human keratinocyte growth factor activity on proliferation and differentiation of human keratinocytes: Differentiation response distinguishes KGF from EGF family

Cited by 214 publications

References 35 publications

Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer

Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer

Pattern of keratinocyte growth factor and keratinocyte growth factor receptor expression during mouse fetal development suggests a role in mediating morphogenetic mesenchymal‐epithelial interactions

Dermatan Sulfate Binds and Potentiates Activity of Keratinocyte Growth Factor (FGF-7)

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