EphB2 Promotes Progression of Cutaneous Squamous Cell Carcinoma

Keratinocyte-derived skin cancer, cutaneous squamous cell carcinoma (cSCC), is the most common metastatic skin cancer. We have examined the role of Eph/ephrin signaling in the progression of cSCC. Analysis of the expression of EPH and EFN families in cSCC cells and normal epidermal keratinocytes revealed overexpression of EPHB2 mRNA in cSCC cells and cSCC tumors in vivo. Tumor cell–specific overexpression of EphB2 was detected in human cSCCs and in chemically induced mouse cSCCs with immunohistochemistry, whereas the expression of EphB2 was low in premalignant lesions and normal skin. Knockdown of EphB2 expression in cSCC cells suppressed growth and vascularization of cSCC xenografts in vivo and inhibited proliferation, migration, and invasion of cSCC cells in culture. EphB2 knockdown downregulated expression of genes associated with biofunctions cell viability, migration of tumor cells, and invasion of tumor cells. Among the genes most downregulated by EphB2 knockdown were MMP1 and MMP13. Moreover, activation of EphB2 signaling by ephrin-B2-Fc enhanced production of invasion proteinases matrix metalloproteinase-13 (MMP13) and MMP1, and invasion of cSCC cells. These findings provide mechanistic evidence for the role of EphB2 in the early progression of cSCC to the invasive stage and identify EphB2 as a putative therapeutic target in this invasive skin cancer

CCHCR1 Is Up-Regulated in Skin Cancer and Associated with EGFR Expression

Peer reviewe

CIP2A Inhibits PP2A in Human Malignancies

SummaryInhibition of protein phosphatase 2A (PP2A) activity has been identified as a prerequisite for the transformation of human cells. However, the molecular mechanisms by which PP2A activity is inhibited in human cancers are currently unclear. In this study, we describe a cellular inhibitor of PP2A with oncogenic activity. The protein, designated Cancerous Inhibitor of PP2A (CIP2A), interacts directly with the oncogenic transcription factor c-Myc, inhibits PP2A activity toward c-Myc serine 62 (S62), and thereby prevents c-Myc proteolytic degradation. In addition to its function in c-Myc stabilization, CIP2A promotes anchorage-independent cell growth and in vivo tumor formation. The oncogenic activity of CIP2A is demonstrated by transformation of human cells by overexpression of CIP2A. Importantly, CIP2A is overexpressed in two common human malignancies, head and neck squamous cell carcinoma (HNSCC) and colon cancer. Thus, our data show that CIP2A is a human oncoprotein that inhibits PP2A and stabilizes c-Myc in human malignancies

Keratinocyte Growth Factor Induces Gene Expression Signature Associated with Suppression of Malignant Phenotype of Cutaneous Squamous Carcinoma Cells

Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes

Age-friendly Tesoma

Toimintakyvyn säilyminen ja itsenäisen selviytymisen tukeminen ovat ikääntyneiden hoidon perustavoitteita. Ikäystävällisessä elinympäristössä alueen asukkaat voivat ikääntyessäänkin osallistua aktiivisesti yhteisön elämään. Esteettömät rakennukset ja jalankulkuystävällinen ympäristö lisäävät omatoimisuutta kuin myös fyysisen, psyykkisen ja sosiaalisen toimintakyvyn säilymistä. Ikääntyneille sopivat asunnot sijaitsevat palveluiden lähellä muun asutuksen joukossa. Diplomityön tavoitteena on suunnitella ikääntyneiden asukkaiden toimintakykyä ja hyvinvointia tukeva elinympäristö. Tampereelle sijoittuva osahanke on osa Aalto-yliopiston arkkitehtuurin laitoksen Sotera-instituutin Muuttuva yhteiskunta – muuttuvat palvelut -hanketta. Tesoma on läntisen Tampereen tärkeimpiä palvelukeskittymiä. Tesoman keskustaa ollaan kehittämässä ikääntyneille soveltuvaksi asuinympäristöksi mm. uuden hyvinvointikeskuksen sekä elinikäistä asumista tukevan elinkaarikorttelin avulla. Kasvavan ikääntyvän väestön tarpeisiin tarvitaan kuitenkin lisää heille sopivia asumisen vaihtoehtoja. Tesoman keskusta-alueen rakennuskanta soveltuu nykyisin huonosti toimintakyvyiltään heikentyneille asukkaille. Myös etäisyydet asunnoista palveluihin ovat pitkiä huonokuntoisille. Alueen liikenneympäristö ei myöskään muodosta jalankulkijan kannalta miellyttävää ympäristöä, joka houkuttelisi lähtemään ulos ja viettämään aikaa alueen keskustassa. Tesoman keskusta-aluetta tiivistämällä luodaan jalankulkuystävällinen ympäristö, jossa ikääntyneille soveltuvat asunnot sijaitsevat palveluiden välittömässä läheisyydessä. Esteetön asuinympäristö ja palveluiden hyvä saavutettavuus tukevat ikääntyneiden kotona asumista ja omatoimista asioiden hoitamista. Lähietäisyydellä sijaitsevat palvelut vähentävät myös autoriippuvuutta. Monipuolinen asuntotarjonta lisää mahdollisuuksia asua tutussa elinympäristössä, ikääntyneiden ei tarvitse muuttaa alueelta pois palvelutarpeen muuttuessa. Suunnitelmassa esitetään noin 86000 kerrosneliömetrin lisärakentamista, jolla mahdollistetaan noin 1600 uuden asukkaan muuttaminen Tesoman keskustaan. Uudet kokoavat ja yhdistävät kaupunkitilat luovat puitteet toiminnoiltaan sekoittuneen ja monimuotoisen kaupunginosakeskuksen syntymiselle. Uudet asuinrakennukset sijoittuvat samoihin kortteleihin palveluiden kanssa tai kävelyetäisyydelle palveluista. Monipuoliset toiminnot luovat puitteet elävälle kaupunkiympäristölle. Suunnitelmassa alueelle tehdään asukkaita kokoavia kaupunkitiloja. Alueen keskelle muodostuvasta kävelykadusta tulee koko aluetta yhdistävä elävä ja suojaisa julkinen kaupunkitila. Turvallinen ja viihtyisä kävely-ympäristö houkuttelee lähtemään ulos. Jalankulkuystävällinen lähiympäristö monipuolisine toimintamahdollisuuksineen lisää sosiaalisen osallistuminen mahdollisuuksia. Lyhyet välimatkat kotoa palveluihin lisäävät myös arkiliikunnan määrää. Näillä puolestaan on myönteisiä vaikutuksia niin fyysiseen kuin psyykkiseenkin terveyteen.The basic goals of the elderly care are to support functional abilities and independent living. In an age-friendly environment, residents of the area can actively participate in community life as they age. Accessible buildings and a pedestrian-friendly environment enhance self-sufficiency as well as the physical, mental and social functional ability. The apartments suitable for elderly people are located near other services and activities. The aim of this thesis is to design the living environment for older people. The thesis is part of the Sotera Institute’s “Muuttuva yhteiskunta – muuttuvat palvelut” project at the Department of Architecture at Aalto University. The Tesoma area in Tampere is the subject of this thesis. Tesoma is a suburban center in western Tampere. Tesoma is being developed as a living environment suitable for the elderly. For example, a new wellness center and housing block for life-long living are being built. However, for the needs of a growing aging population, additional housing choices are needed. The current housing blocks in the Tesoma area suit frail residents poorly. In addition, distances from apartments to services are too long for the infirm. The traffic environment in the area does not make pleasant surroundings for a pedestrian who would be tempted to go out and spend time in the center of the area. The center of Tesoma is supplemented with new infill buildings to create a pedestrian-friendly environment where homes for older people are located in the immediate proximity of the services. An accessible residential environment and good accessibility of the services support the self-care and lives of the elderly in their own homes. Closely situated services also reduce car-dependence. The versatile housing supply increases the chances of living in a familiar environment, and the elderly need not move from the area when they need additional services. The plan proposes development of 86000 square meters of new floor area, which provides apartments for 1600 new inhabitants in Tesoma. The new gathering and connecting urban spaces create a framework for the creation of a mixed and multifunctional suburban center. New residential buildings are located in the same blocks with services or within a walking distance of the services. Versatile functions create a framework for living in the urban environment. In this plan, new urban areas are being designed in the area. The pedestrian zone in the middle of the area becomes a living and safe public urban space that connects the entire area. A safe and comfortable walking environment encourages residents to go out. The pedestrian-friendly neighborhood with its versatile possibilities of action increases the opportunities for social participation. Short distances from home to services also increase the possibilities for everyday physical exercise. These, in turn, have positive effects on both physical and psychological health

Expression of Human Macrophage Metalloelastase (MMP-12) by Tumor Cells in Skin Cancer

Matrix metalloproteinases play an essential role in tumor growth and invasion. Different matrix metalloproteinases are often expressed in cancers with distinct patterns. To investigate the role of human macrophage metalloelastase (MMP-12) in epidermal tumors, we studied human macrophage metalloelastase mRNA and protein expression in malignant squamous cell and basal cell carcinomas, and in premalignant Bowen's disease. Human macrophage metalloelastase was detected in 11 of 17 squamous cell carcinomas in epithelial cancer cells, whereas macrophages were positive in 15 of 17 samples. In basal cell carcinomas, human macrophage metalloelastase was more often found in macrophages (seven of 19) than in cancer cells (four of 19). Human macrophage metalloelastase mRNA was also detected in three cell lines derived from squamous cell carcinomas of the head and neck and in transformed HaCaT cells, whereas premalignant tumors and primary keratinocytes were negative for human macrophage metalloelastase mRNA. Western analysis revealed human macrophage metalloelastase protein in squamous cell carcinoma cells. Our results show that human macrophage metalloelastase can be expressed in vivo and in vitro by transformed epithelial cells and indicate that the level of human macrophage metalloelastase expression correlates with epithelial dedifferentiation and histologic aggressiveness

The expression of matrilin 2, CXCL10, IGFBP3, DUSP4 and DUSP6 is regulated by KGF in cutaneous SCC cells.

<p>Cutaneous SCC cell lines (UT-SCC-7, -12A, -59A, -91A, -105, -111, -115, and -118), HaCaT cells and normal keratinocytes (NHEK PC, Kerat45B) were serum starved, treated with recombinant KGF (rKGF; 10 ng/ml) for 24 h and analyzed for (<b>A</b>) matrilin 2, CXCL10 and IGFBP3 mRNA and (<b>B</b>) DUSP4 and DUSP6 mRNA expression with qPCR. The results were normalized for β-actin mRNA levels in each sample. Note that the cell lines UT-SCC-91A and UT-SCC-111 do not express KGFR mRNA. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001, with independent samples T-test, n = 3–4.</p