Obstetrician & Gynecologist (OB/GYN), Radiologist
19 years of experience
Video profile
Accepting new patients
571 W Main St
Ste 200
Lewisville, TX 75057
972-221-8588
Locations and availability (3)

Education ?

Medical School Score
The University of Texas Southwestern (1991)
  • Currently 1 of 4 apples

Awards & Distinctions ?

Associations
American Board of Obstetrics and Gynecology

Affiliations ?

Dr. Owens is affiliated with 7 hospitals.

Hospital Affilations

Score

Rankings

  • Baylor Medical Center At Irving
    1901 N MacArthur Blvd, Irving, TX 75061
    • Currently 4 of 4 crosses
    Top 25%
  • UT Southwestern University Hospital - Zale Lipshy
    5151 Harry Hines Blvd, Dallas, TX 75235
    • Currently 4 of 4 crosses
    Top 25%
  • Medical Center Of Lewisville
    500 W Main St, Lewisville, TX 75057
    • Currently 3 of 4 crosses
    Top 50%
  • Las Colinas Medical Center
    6800 N MacArthur Blvd, Irving, TX 75039
    • Currently 2 of 4 crosses
  • Parkland Health & Hospital System
    5201 Harry Hines Blvd, Dallas, TX 75235
    • Currently 1 of 4 crosses
  • Baylor Surgicare
  • UT Southwestern St. Paul Hospital
  • Publications & Research

    Dr. Owens has contributed to 30 publications.
    Title C/ebpα Expression is Downregulated in Human Nonmelanoma Skin Cancers and Inactivation of C/ebpα Confers Susceptibility to Uvb-induced Skin Squamous Cell Carcinomas.
    Date July 2011
    Journal The Journal of Investigative Dermatology
    Excerpt

    Human epidermis is routinely subjected to DNA damage induced by UVB solar radiation. Cell culture studies have revealed an unexpected role for C/EBPα (CCAAT/enhancer-binding protein-α) in the DNA damage response network, where C/EBPα is induced following UVB DNA damage, regulates the G(1) checkpoint, and diminished or ablated expression of C/EBPα results in G(1) checkpoint failure. In the current study we observed that C/EBPα is induced in normal human epidermal keratinocytes and in the epidermis of human subjects exposed to UVB radiation. The analysis of human skin precancerous and cancerous lesions (47 cases) for C/EBPα expression was conducted. Actinic keratoses, a precancerous benign skin growth and precursor to squamous cell carcinoma (SCC), expressed levels of C/EBPα similar to normal epidermis. Strikingly, all invasive SCCs no longer expressed detectable levels of C/EBPα. To determine the significance of C/EBPα in UVB-induced skin cancer, SKH-1 mice lacking epidermal C/EBPα (CKOα) were exposed to UVB. CKOα mice were highly susceptible to UVB-induced SCCs and exhibited accelerated tumor progression. CKOα mice displayed keratinocyte cell cycle checkpoint failure in vivo in response to UVB that was characterized by abnormal entry of keratinocytes into S phase. Our results demonstrate that C/EBPα is silenced in human SCC and loss of C/EBPα confers susceptibility to UVB-induced skin SCCs involving defective cell cycle arrest in response to UVB.

    Title Identification of Epidermal Progenitors for the Merkel Cell Lineage.
    Date December 2010
    Journal Development (cambridge, England)
    Excerpt

    Epithelial stem cells in adult mammalian skin are known to maintain epidermal, follicular and sebaceous lineages during homeostasis. Recently, Merkel cell mechanoreceptors were identified as a fourth lineage derived from the proliferative layer of murine skin epithelium; however, the location of the stem or progenitor population for Merkel cells remains unknown. Here, we have identified a previously undescribed population of epidermal progenitors that reside in the touch domes of hairy skin, termed touch dome progenitor cells (TDPCs). TDPCs are epithelial keratinocytes and are distinguished by their unique co-expression of α6 integrin, Sca1 and CD200 surface proteins. TDPCs exhibit bipotent progenitor behavior as they give rise to both squamous and neuroendocrine epidermal lineages, whereas the remainder of the α6(+) Sca1(+) CD200(-) epidermis does not give rise to Merkel cells. Finally, TDPCs possess a unique transcript profile that appears to be enforced by the juxtaposition of TDPCs with Merkel cells within the touch dome niche.

    Title Zinc Fixation Preserves Flow Cytometry Scatter and Fluorescence Parameters and Allows Simultaneous Analysis of Dna Content and Synthesis, and Intracellular and Surface Epitopes.
    Date October 2010
    Journal Cytometry. Part A : the Journal of the International Society for Analytical Cytology
    Excerpt

    Zinc salt-based fixation (ZBF) has proved advantageous in histochemical analyses conducted on intact tissues but has not been exploited in flow cytometry procedures that focus on quantitative analysis of individual cells. Here, we show that ZBF performs equally well to paraformaldehyde in the preservation of surface epitope labeling and forward and side scatter parameters as measured by flow cytometry. ZBF-fixed mouse epithelial keratinocytes exhibit a staining pattern for the surface markers Sca-1, CD34 and alpha6 integrin that is highly analogous to live cells. Furthermore, ZBF also preserves DNA allowing subsequent quantitative PCR analysis or labeling for incorporation of the thymidine analog EdU following surface and intracellular epitope staining. Finally, ZBF treatment allows for long-term storage of labeled cells with little change in these parameters. Thus, we present a protocol for zinc salt fixation of cells that allows for the simultaneous analysis of DNA and intracellular and cell surface proteins by flow cytometry.

    Title Cross-talk Between the P38alpha and Jnk Mapk Pathways Mediated by Map Kinase Phosphatase-1 Determines Cellular Sensitivity to Uv Radiation.
    Date September 2010
    Journal The Journal of Biological Chemistry
    Excerpt

    MAPK phosphatase-1 (DUSP1/MKP-1) is a mitogen and stress-inducible dual specificity protein phosphatase, which can inactivate all three major classes of MAPK in mammalian cells. DUSP1/MKP-1 is implicated in cellular protection against a variety of genotoxic insults including hydrogen peroxide, ionizing radiation, and cisplatin, but its role in the interplay between different MAPK pathways in determining cell death and survival is not fully understood. We have used pharmacological and genetic tools to demonstrate that DUSP1/MKP-1 is an essential non-redundant regulator of UV-induced cell death in mouse embryo fibroblasts (MEFs). The induction of DUSP1/MKP-1 mRNA and protein in response to UV radiation is mediated by activation of the p38alpha but not the JNK1 or JNK2 MAPK pathways. Furthermore, we identify MSK1 and -2 and their downstream effectors cAMP-response element-binding protein/ATF1 as mediators of UV-induced p38alpha-dependent DUSP1/MKP-1 transcription. Dusp1/Mkp-1 null MEFs display increased signaling through both the p38alpha and JNK MAPK pathways and are acutely sensitive to UV-induced apoptosis. This lethality is rescued by the reintroduction of wild-type DUSP1/MKP-1 and by a mutant of DUSP1/MKP-1, which is unable to bind to either p38alpha or ERK1/2, but retains full activity toward JNK. Importantly, whereas small interfering RNA-mediated knockdown of DUSP1/MKP-1 sensitizes wild-type MEFs to UV radiation, DUSP1/MKP-1 knockdown in MEFS lacking JNK1 and -2 does not result in increased cell death. Our results demonstrate that cross-talk between the p38alpha and JNK pathways mediated by induction of DUSP1/MKP-1 regulates the cellular response to UV radiation.

    Title The Immunosuppressive Surface Ligand Cd200 Augments the Metastatic Capacity of Squamous Cell Carcinoma.
    Date May 2010
    Journal Cancer Research
    Excerpt

    CD200 (OX-2) is a cell surface glycoprotein that imparts immune privileges by suppressing alloimmune and autoimmune responses through its receptor, CD200R, expressed primarily on myeloid cells. The ability of CD200 to suppress myeloid cell activation is critical for maintaining normal tissue homeostasis but may also enhance the survival of migratory neoplastic cells. We show that CD200 expression is largely absent in well-differentiated primary squamous cell carcinoma (SCC) of the skin, but is highly induced in SCC metastases to the lymph node and other solid tissues. CD200 does not influence the proliferative or invasive capacity of SCC cells or their ability to reconstitute primary skin tumors. However, loss of CD200 impairs the ability of SCC cells to metastasize and seed secondary tumors, indicating that the survival of CD200(+) SCC cells may depend on their ability to interact with CD200R(+) immune cells. The predominant population of CD200R(+) stromal cells was CD11b(+)Gr-1(+) myeloid-derived suppressor cells, which release elevated levels of granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor when in the presence of SCC cells in a CD200-dependent manner. Collectively, our findings implicate CD200 as a hallmark of SCC metastasis and suggest that the ability of CD200(+) SCC keratinocytes to directly engage and modulate CD200R(+) myeloid-derived suppressor cells is essential to metastatic survival.

    Title Tcf Proteins Are Deeply Rooted in Skin.
    Date October 2009
    Journal Nature Genetics
    Title The Mutant Form of Lamin A That Causes Hutchinson-gilford Progeria is a Biomarker of Cellular Aging in Human Skin.
    Date August 2008
    Journal Plos One
    Excerpt

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.

    Title Epidermal Expression of the Truncated Prelamin A Causing Hutchinson-gilford Progeria Syndrome: Effects on Keratinocytes, Hair and Skin.
    Date August 2008
    Journal Human Molecular Genetics
    Excerpt

    Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by point mutation in LMNA encoding A-type nuclear lamins. The mutations in LMNA activate a cryptic splice donor site, resulting in expression of a truncated, prenylated prelamin A called progerin. Expression of progerin leads to alterations in nuclear morphology, which may underlie pathology in HGPS. We generated transgenic mice expressing progerin in epidermis under control of a keratin 14 promoter. The mice had severe abnormalities in morphology of skin keratinocyte nuclei, including nuclear envelope lobulation and decreased nuclear circularity not present in transgenic mice expressing wild-type human lamin A. Primary keratinocytes isolated from these mice had a higher frequency of nuclei with abnormal shape compared to those from transgenic mice expressing wild-type human lamin A. Treatment with a farnesyltransferase inhibitor significantly improved nuclear shape abnormalities and induced the formation of intranuclear foci in the primary keratinocytes expressing progerin. Similarly, spontaneous immortalization of progerin-expressing cultured keratinocytes selected for cells with normal nuclear morphology. Despite morphological alterations in keratinocyte nuclei, mice expressing progerin in epidermis had normal hair grown and wound healing. Hair and skin thickness were normal even after crossing to Lmna null mice to reduce or eliminate expression of normal A-type lamins. Although progerin induces significant alterations in keratinocyte nuclear morphology that are reversed by inhibition of farnesyltransferasae, epidermal expression does not lead to alopecia or other skin abnormalities typically seen in human subjects with HGPS.

    Title A Distinct Population of Clonogenic and Multipotent Murine Follicular Keratinocytes Residing in the Upper Isthmus.
    Date July 2008
    Journal Journal of Cell Science
    Excerpt

    The bulge region of adult murine hair follicles harbors epidermal stem cells with multipotent capacity; however, the restricted contributions of these cells under homeostatic conditions indicates that additional stem or progenitor cell populations may be required to maintain squamous and sebaceous lineages. We have identified a distinct population of murine hair follicle keratinocytes residing in the upper isthmus (UI) between the infundibulum and bulge regions that are distinguished by low alpha6 integrin levels and are negative for CD34 and Sca-1. Purified UI cells give rise to long-term, stable epidermal, follicular and sebaceous lineages and can self-renew in vivo. These cells are non-quiescent and possess a unique transcript profile compared with bulge stem cells and may represent a distinct reservoir of epidermal stem or progenitor cells.

    Title Negative-feedback Regulation of Fgf Signalling by Dusp6/mkp-3 is Driven by Erk1/2 and Mediated by Ets Factor Binding to a Conserved Site Within the Dusp6/mkp-3 Gene Promoter.
    Date July 2008
    Journal The Biochemical Journal
    Excerpt

    DUSP6 (dual-specificity phosphatase 6), also known as MKP-3 [MAPK (mitogen-activated protein kinase) phosphatase-3] specifically inactivates ERK1/2 (extracellular-signal-regulated kinase 1/2) in vitro and in vivo. DUSP6/MKP-3 is inducible by FGF (fibroblast growth factor) signalling and acts as a negative regulator of ERK activity in key and discrete signalling centres that direct outgrowth and patterning in early vertebrate embryos. However, the molecular mechanism by which FGFs induce DUSP6/MKP-3 expression and hence help to set ERK1/2 signalling levels is unknown. In the present study, we demonstrate, using pharmacological inhibitors and analysis of the murine DUSP6/MKP-3 gene promoter, that the ERK pathway is critical for FGF-induced DUSP6/MKP-3 transcription. Furthermore, we show that this response is mediated by a conserved binding site for the Ets (E twenty-six) family of transcriptional regulators and that the Ets2 protein, a known target of ERK signalling, binds to the endogenous DUSP6/MKP-3 promoter. Finally, the murine DUSP6/MKP-3 promoter coupled to EGFP (enhanced green fluorescent protein) recapitulates the specific pattern of endogenous DUSP6/MKP-3 mRNA expression in the chicken neural plate, where its activity depends on FGFR (FGF receptor) and MAPK signalling and an intact Ets-binding site. These findings identify a conserved Ets-factor-dependent mechanism by which ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling.

    Title P53, Chemokines, and Squamous Cell Carcinoma.
    Date September 2007
    Journal The Journal of Clinical Investigation
    Excerpt

    The genetic and epigenetic events underlying cutaneous squamous cell carcinoma (SCC) have been actively studied; however, no resulting preventative or therapeutic strategies have successfully targeted this lesion, apart from surgery. In this issue of the JCI, two novel regulators of SCC pathogenesis are introduced, gain-of-function mutations in the p53 gene, reported by Caulin et al., and chemokine sequestration by the D6 receptor, reported by Nibbs et al. (see the related articles beginning on pages 1884 and 1893, respectively). These studies provide new twists and insights into the development of this potentially lethal disease.

    Title Differential Regulation of Map Kinase Signalling by Dual-specificity Protein Phosphatases.
    Date June 2007
    Journal Oncogene
    Excerpt

    The regulated dephosphorylation of mitogen-activated protein kinases (MAPKs) plays a key role in determining the magnitude and duration of kinase activation and hence the physiological outcome of signalling. In mammalian cells, an important component of this control is mediated by the differential expression and activities of a family of 10 dual-specificity (Thr/Tyr) MAPK phosphatases (MKPs). These enzymes share a common structure in which MAPK substrate recognition is determined by sequences within an amino-terminal non-catalytic domain whereas MAPK binding often leads to a conformational change within the C-terminal catalytic domain resulting in increased enzyme activity. MKPs can either recognize and inactivate a single class of MAP kinase, as in the specific inactivation of extracellular signal regulated kinase (ERK) by the cytoplasmic phosphatase DUSP6/MKP-3 or can regulate more than one MAPK pathway as illustrated by the ability of DUSP1/MKP-1 to dephosphorylate ERK, c-Jun amino-terminal kinase and p38 in the cell nucleus. These properties, coupled with transcriptional regulation of MKP expression in response to stimuli that activate MAPK signalling, suggest a complex negative regulatory network in which individual MAPK activities can be subject to negative feedback control, but also raise the possibility that signalling through multiple MAPK pathways may be integrated at the level of regulation by MKPs.

    Title Dual Role of Inactivating Lef1 Mutations in Epidermis: Tumor Promotion and Specification of Tumor Type.
    Date May 2007
    Journal Cancer Research
    Excerpt

    The NH(2) terminus of LEF1 is frequently mutated in human sebaceous tumors. To investigate how this contributes to cancer, we did two-stage chemical carcinogenesis on K14DeltaNLef1 transgenic mice, which express NH(2)-terminally truncated Lef1 in the epidermal basal layer. Transgenic mice developed more tumors, more rapidly than littermate controls, even without exposure to tumor promoter. They developed sebaceous tumors, whereas controls developed squamous cell carcinomas. K14DeltaNLef1 epidermis failed to up-regulate p53 and p21 proteins during tumorigenesis or in response to UV irradiation, and this correlated with impaired p14ARF induction. We propose that LEF1 NH(2)-terminal mutations play a dual role in skin cancer, specifying tumor type by inhibiting Wnt signaling and acting as a tumor promoter by preventing induction of p53.

    Title Suprabasal Alpha 5 Beta1 Integrin Expression Stimulates Formation of Epidermal Squamous Cell Carcinomas Without Disrupting Tgfbeta Signaling or Inducing Spindle Cell Tumors.
    Date September 2005
    Journal Molecular Carcinogenesis
    Excerpt

    During epidermal chemical carcinogenesis benign papillomas convert to squamous cell carcinomas, some of which undergo epithelial-mesenchymal conversion to highly malignant spindle cell tumors. TGFbeta inhibits early stages of carcinogenesis but promotes the spindle cell phenotype in later stages. One hallmark of spindle cell tumors is upregulation of the alpha 5 beta 1 integrin fibronectin receptor. To examine the significance of altered alpha 5 beta1 integrin expression, we induced tumors in transgenic mice expressing alpha 5 beta1 in the suprabasal epidermal layers. Invalpha 5 beta1 mice developed threefold more papillomas and squamous cell carcinomas than wild-type (Wt) littermates; however, no spindle cell tumors or increased metastases were observed. Suprabasal expression of the alpha 6 beta 4 integrin increases squamous cell carcinoma formation and decreases TGFbeta sensitivity while alpha 3 beta1 may have the opposite effect. In contrast, nuclear phosphoSmad2 labeling in Invalpha 5 beta1 epidermis and tumors was indistinguishable from Wt, and suprabasal alpha 5 beta1 did not block TGFbeta-induced Smad2/3 translocation or growth inhibition in cultured keratinocytes. We conclude that upregulation of alpha 5 beta1 does not predispose the epidermis to undergo conversion to spindle cell tumors and that the mechanism by which alpha 5 beta1 influences susceptibility to carcinogenesis is independent of perturbed TGFbeta signaling.

    Title Suprabasal Alpha6beta4 Integrin Expression in Epidermis Results in Enhanced Tumourigenesis and Disruption of Tgfbeta Signalling.
    Date May 2004
    Journal Journal of Cell Science
    Excerpt

    Inappropriate alpha6beta4 integrin expression correlates with a high risk of tumour progression in stratified squamous epithelia. Targeted expression of alpha6beta4 in the suprabasal layers of transgenic mouse epidermis dramatically increased the frequency of papillomas, carcinomas and metastases induced by chemical carcinogenesis, independent of the beta4 cytoplasmic domain. Suprabasal alpha6beta4 also perturbed transforming growth factor beta (TGFbeta) signalling as demonstrated by decreased nuclear Smad2 in transgenic epidermis and tumours. In cultured keratinocytes, suprabasal alpha6beta4 relieved TGFbeta-mediated growth inhibition and blocked nuclear translocation of activated Smad2/3. Responsiveness to TGFbeta could be restored by inhibiting cadherin-mediated cell-cell adhesion or phosphoinositide 3-kinase (PI3-K) activity, but not by inhibiting mitogen-activated protein kinase (MAPK) activity. These data suggest that suprabasal alpha6beta4 promotes tumourigenesis by preventing TGFbeta from suppressing clonal expansion of initiated cells in the epidermal basal layer.

    Title Contribution of Stem Cells and Differentiated Cells to Epidermal Tumours.
    Date July 2003
    Journal Nature Reviews. Cancer
    Excerpt

    The outer covering of the skin--the epidermis--is subject to sustained environmental assaults. As a result, many cells acquire potentially oncogenic mutations. Most cells are lost through differentiation, and only long-term epidermal residents, such as stem cells, accumulate the number of genetic hits that are necessary for tumour development. So, what genetic and environmental factors determine whether a mutant stem cell forms a tumour and what type of tumour will develop?

    Title Tumour Necrosis Factor-alpha Mediates Tumour Promotion Via a Pkc Alpha- and Ap-1-dependent Pathway.
    Date July 2002
    Journal Oncogene
    Excerpt

    Tumour necrosis factor-alpha (TNF-alpha) deficient mice (TNF-alpha(-/-) mice) are resistant to skin carcinogenesis. Cellular signalling via the transcription factor complex AP-1 is thought to play a key role in tumour promotion. The induction of a specific subset of AP-1 responsive genes thought to be important for tumour development, namely GM-CSF, MMP-9 and MMP-3, was suppressed in TNF-alpha(-/-) compared to wild-type mouse skin in response to the tumour promotor TPA. The differential induction of these genes correlated with a temporal shift in AP-1 activation and c-Jun expression in TNF-alpha(-/-) compared to wild-type epidermis. The major receptor for TPA-induced signalling in basal keratinocytes, PKC alpha, was also differentially regulated in wild-type compared with TNF-alpha(-/-) epidermis. A marked delay in TPA-induced intracellular translocation and downregulation of PKC alpha was observed in TNF-alpha(-/-) epidermis, which correlated with the deregulated TPA-induced AP-1 activation and c-Jun expression. The frequency of DNA adduct formation and c-Ha-ras mutations was the same in wild-type and TNF-alpha(-/-) epidermis after DMBA treatment, suggesting that TNF-alpha was not involved in tumour initiation. These data suggest that the pro-inflammatory cytokine TNF-alpha is a critical mediator of tumour promotion, acting via a PKC alpha- and AP-1-dependent pathway. This may be one mechanism by which chronic inflammation increases susceptibility to cancer.

    Title Expression of Deltanlef1 in Mouse Epidermis Results in Differentiation of Hair Follicles into Squamous Epidermal Cysts and Formation of Skin Tumours.
    Date February 2002
    Journal Development (cambridge, England)
    Excerpt

    To examine the consequences of repressing beta-catenin/Lef1 signalling in mouse epidermis, we expressed a DeltaNLef1 transgene, which lacks the beta-catenin binding site, under the control of the keratin 14 promoter. No skin abnormalities were detected before the first postnatal hair cycle. However, from 6 weeks of age, mice underwent progressive hair loss which correlated with the development of dermal cysts. The cysts were derived from the base of the hair follicles and expressed morphological and molecular markers of interfollicular epidermis. Adult mice developed spontaneous skin tumours, most of which exhibited sebaceous differentiation, which could be indicative of an origin in the upper part of the hair follicle. The transgene continued to be expressed in the tumours and beta-catenin signalling was still inhibited, as evidenced by absence of cyclin D1 expression. However, patched mRNA expression was upregulated, suggesting that the sonic hedgehog pathway might play a role in tumour formation. Based on our results and previous data on the consequences of activating beta-catenin/Lef1 signalling in postnatal keratinocytes, we conclude that the level of beta-catenin signalling determines whether keratinocytes differentiate into hair or interfollicular epidermis, and that perturbation of the pathway by overexpression of DeltaNLef1 can lead to skin tumour formation.

    Title Influence of Beta1 Integrins on Epidermal Squamous Cell Carcinoma Formation in a Transgenic Mouse Model: Alpha3beta1, but Not Alpha2beta1, Suppresses Malignant Conversion.
    Date July 2001
    Journal Cancer Research
    Excerpt

    Although aberrant integrin expression has been documented in many epithelial tumors, little is known about how integrins influence neoplastic progression. To examine this issue, transgenic mice in which the alpha2beta1 or alpha3beta1 integrin was expressed in the suprabasal epidermal layers via the involucrin promoter were subjected to skin carcinogenesis. Equal numbers of benign squamous papillomas were observed in transgenic and wild-type animals. However, the frequency of conversion of papillomas to malignant squamous cell carcinomas was much lower in alpha3beta1 transgenic than in alpha2beta1 transgenic and wild-type mice. No differences were observed in apoptosis or in the expression of endogenous integrins in transgenic and wild-type papillomas. However, alpha3beta1 transgenic papillomas displayed a diminished proliferative capacity and were more highly differentiated as judged by BrdUrd incorporation and keratin 10 expression, respectively, than alpha2beta1 transgenic and wild-type papillomas. Two proteins that associate with alpha3beta1 and not alpha2beta1 are extracellular matrix metalloproteinase inducer and CD81. Extracellular matrix metalloproteinase inducer expression correlated inversely with the degree of differentiation in normal epidermis and in transgenic and wild-type papillomas. Up-regulation of CD81 was observed in 100% of wild-type and 88% of alpha2beta1 transgenic papillomas but in only 25% of alpha3beta1 transgenic papillomas. CD81 was undetectable in untreated epidermis and strongly expressed in all transgenic and wild-type squamous cell carcinomas. Our results demonstrate that the alpha3beta1 integrin can suppress malignant conversion, and that the mechanism may involve CD81.

    Title Expression of Involucrin in Normal, Hyperproliferative and Neoplastic Mouse Keratinocytes.
    Date May 2001
    Journal Experimental Dermatology
    Excerpt

    Involucrin is a protein precursor of the epidermal cornified envelope. Although expression of the human protein has been documented extensively, studies in the mouse have been hampered by a shortage of good antibodies. We describe the production of recombinant mouse involucrin and preparation of rabbit antisera to the protein that work well by immunohistochemistry and Western blotting. We confirm that in normal mouse epidermis the onset of involucrin expression is in the upper spinous layers and inner root sheath of the hair follicle. Involucrin was also detected in the differentiating epithelial cells of normal tongue, oesophagus and bladder. Involucrin was expressed in a subpopulation of mouse keratinocytes cultured in standard or low calcium medium and the proportion of involucrin-positive cells increased during suspension-induced terminal differentiation. Western blotting of keratinocytes from several inbred mouse strains revealed a remarkable heterogeneity in the electrophoretic mobility of involucrin, reflecting inter-strain variation in the number of tandem repeats in the protein. In the hyperproliferative epidermis of healing wounds involucrin was expressed in most of the suprabasal layers. In epidermal papillomas and carcinomas involucrin expression correlated well with degree of histological differentiation. The sites of expression of the mouse protein were thus the same as those previously reported for human involucrin. With the development of the new antibodies we anticipate that involucrin will become as widely used a marker of keratinocyte differentiation in the mouse as it is in the human.

    Title A Multihit, Multistage Model of Chemical Carcinogenesis.
    Date September 1999
    Journal Carcinogenesis
    Excerpt

    Carcinogenesis involves the accumulation of genetic changes within a single cell. Tumor promotion functions in the initial clonal expansion of an initiated cell but is generally not considered to influence later stages. To investigate whether tumor promotion can influence later stages of carcinogenesis we developed a two-hit 7, 12-dimethylbenz[a]anthracene (D) protocol designed to enrich for keratinocytes that contain at least two D-induced genetic alterations. FVB/N mice were initiated with D and promoted with 12-O-tetradecanoylphorbol-13-acetate (T) or treated with acetone (A) vehicle for 6 weeks. At 7 weeks after the start of promotion, but before visible papilloma development, groups of mice were treated with a second dose of D or A and 1 week later T promotion was resumed. D/T/A/T mice developed 2.8 papillomas/mouse and D/A/D/T mice demonstrated an additive tumor response and developed 5.8 papillomas/mouse. Importantly, D/T/D/T mice developed 12.4 papillomas/mouse, thereby demonstrating a synergistic tumor response compared with D/A/D/T and D/T/A/T mice. D/T/D/T papillomas exhibited increases in suprabasal S phase cells and keratin 13 expression when compared with D/T/A/T papillomas. D/T/D/T mice developed squamous cell carcinomas (SCCs) 10 weeks earlier than D/T/A/T mice and demonstrated a 96% malignancy incidence and 1.71 SCC/mouse compared with D/T/A/T mice, which demonstrated a 28% malignancy incidence and 0.32 SCC/mouse. Greater than 90% of D/T/A/T and D/T/D/T papillomas and SCCs contained mutant Ha-ras, while a normal Ha-ras allele persisted in all cases, indicating that a gene other than the remaining normal allele of Ha-ras was a target gene for the second D hit. These data demonstrate that: (i) promotion between the first and second hits has a profound outcome on carcinogenesis, presumably by increasing the probability that a second hit will occur in a previously initiated cell; (ii) continued promotion after the second hit is required for full expression of malignancy; (iii) the classic initiation-promotion protocol can be extended to a multihit, multistage model.

    Title Mice Deficient in Tumor Necrosis Factor-alpha Are Resistant to Skin Carcinogenesis.
    Date July 1999
    Journal Nature Medicine
    Excerpt

    Given the associations between chronic inflammation and epithelial cancer, we studied susceptibility to skin carcinogenesis in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant to development of benign and malignant skin tumors, whether induced by initiation with DMBA and promotion with TPA or by repeated dosing with DMBA. TNF-alpha(-/-) mice developed 5-10% the number of tumors developed by wild-type mice during initiation/promotion and 25% of those in wild-type mice after repeated carcinogen treatment. TNF-alpha could influence tumor and stromal cells during tumor development. The early stages of TPA promotion are characterized by keratinocyte hyperproliferation and inflammation. These were diminished in TNF-alpha(-/-) mice. TNF-alpha was extensively induced in the epidermis, but not the dermis, in TPA-treated wild-type skin, indicating that dermal inflammation is controlled by keratinocyte TNF-alpha production. Deletion of a TNF-alpha inducible chemokine also conferred some resistance to skin tumor development. TNF-alpha has little influence on later stages of carcinogenesis, as tumors in wild-type and TNF-alpha(-/-) mice had similar rates of malignant progression. These data provide evidence that a pro-inflammatory cytokine is required for de novo carcinogenesis and that TNF-alpha is important to the early stages of tumor promotion. Strategies that neutralize TNF-alpha production may be useful in cancer treatment and prevention.

    Title Characterization of Olfactory Deficits in the Rat Following Administration of 2,6-dichlorobenzonitrile (dichlobenil), 3,3'-iminodipropionitrile, or Methimazole.
    Date December 1996
    Journal Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology
    Excerpt

    The histopathology of the olfactory mucosal lesion associated with ip administration of 2,6-dichlorobenzonitrile (dichlobenil) and 3,3'-iminodipropionitrile (IDPN) has been well documented. Whether there is an olfactory deficit associated with the partial loss of the olfactory mucosa (localized around the dorsal medial meatus of the nasal cavity) has yet to be determined. Dichlobenil (100 mg/kg) or IDPN (200 mg/kg) was administered ip to adult male Long-Evans rats previously trained in an olfactory task to find a food pellet buried in approximately 7.5 cm of bedding in a 0.61 x 1.2 x 0.61-m Plexiglass chamber. As a positive control, another group received 300 mg/kg ip of 1-methyl-2-mercaptoimidazole (methimazole), a dosing regimen which destroys nearly all of the olfactory mucosa. All three compounds caused a transient increase in the mean latency to find the pellet, with the magnitude of the effect positively correlated with the extent of the olfactory lesion. In order to determine whether these deficits resulted from olfactory dysfunction or impaired cognitive function (a deficit previously attributed to IDPN exposure), another group of rats was dosed as above and tested in another spatial memory task, the Morris water maze (MWM), which is less dependent upon olfactory function. No performance deficit was detected in the MWM. These data suggest that the transient olfactory deficit in the dichlobenil-, IDPN-, and methimazole-treated rats is attributable to defective olfactory function.

    Title Localization and Expression of Cornifin-alpha/sprr1 in Mouse Epidermis, Anagen Hair Follicles, and Skin Neoplasms.
    Date June 1996
    Journal The Journal of Investigative Dermatology
    Excerpt

    Recently, cornifin-alpha/SPPR1 has been identified as a putative precursor protein of the cornified cell envelope. In this study, the expression and localization of cornifin-alpha/SPPR1 was examined in untreated and tumor promoter-treated mouse skin, hair follicles, and skin neoplasms. Western analysis with antiserum (SQ37A) to a rabbit cornifin-alpha peptide or antiserum (SQ37C) to a human SPRR1 peptide demonstrated a 31-kDa immunoreactive protein in mouse epidermis and Northern analysis revealed the presence of a 1-kb mRNA. Immunohistochemical staining of mouse skin with SQ37A or SQ37C revealed intense and specific staining of the infundibulum, isthmus, and of Henle's layer of the inner root sheath of the lower anagen hair follicle and weak staining of the telogen follicle and the suprabasal layers of the epidermis. Treatment of mouse skin with 12-0-tetradecanoyl-phorbol-13-acetate (TPA) produced a large increase in cornifin-alpha/SPRR1 protein and mRNA. Immunohistochemical localization of cornifin-alpha/SPRR1 in TPA-treated skin indicated that cornifin-alpha/SPRR1 was increased in the suprabasal epidermis but not in the follicle. sn-1,2,-didecanoylglycerol, a model lipid second messenger, produced an increase in cornifin-alpha/SPRR1 protein similar to that of TPA, while mirex, a non-phorbol ester-type promoter had no effect. Topical doses of retinoic acid did not repress TPA-induced cornifin-alpha/SPRR1 expression. Papillomas demonstrated a 10- and 100-fold increase in cornifin-alpha/SPRR1 protein and mRNA, and expression was restricted to suprabasal cells. Squamous cell carcinomas exhibited an intermediate level of cornifin-alpha protein, and expression was restricted to keratinized areas. These data indicate: i) cornifin-alpha/SPRR1 is expressed in mouse skin; ii) cornifin-alpha/SPRR1 is localized to specific areas of the anagen hair follicle with weak staining in the telogen follicle and epidermis; iii) epidermal cornifin-alpha/SPRR1 expression is induced by phorbol ester and sn-1,2-didecanoylglycerol but not mirex, and iv) papillomas and squamous cell carcinomas demonstrate a constitutive increase in cornifin-alpha/SPRR1 in differentiated areas of the neoplasms.

    Title Distribution of Microsomal Epoxide Hydrolase and Glutathione S-transferase in the Rat Olfactory Mucosa: Relevance to Distribution of Lesions Caused by Systemically-administered Olfactory Toxicants.
    Date March 1996
    Journal Chemical Senses
    Excerpt

    This study represents part an of ongoing effort to understand the mechanism underlying the distribution of the olfactory mucosal lesion resulting from the systemic administration of compounds such as 2,6-dichlorobenzonitrile (dichlobenil) and beta,beta'-iminodipropionitrile (IDPN). Immunohistochemistry was performed to localize the microsomal form of epoxide hydrolase (mEH) and glutathione S-transferase (GST) isozymes alpha, mu and pi in the rodent olfactory mucosa. GST-pi was found in abundance in the Bowman's glands of the mucosa lining the dorsal medial meatus (DMM) of the nasal cavity and in the nuclei of basal and sustentacular cells of the dorsal and lateral nasal cavity. Liver and olfactory mucosal levels of mEH are equivalent by Western blot analysis. mEH appeared to be localized in the apical cytoplasm of sustentacular cells in all regions of the olfactory mucosa except for the epithelium lining the DMM. These observations, coupled with the known profile of metabolites for dichlobenil, suggest that systemically-administered compounds causing site-specific lesions in the epithelium lining the DMM of the nasal cavity may do so by the in situ production of reactive epoxide metabolites which are then poorly capable of being detoxified. Thus, the distribution of metabolic enzymes, rather than the absolute level of an enzyme in a tissue, may dictate lesion distribution in the case of toxicants which are bioactivated in target tissues.

    Title Genetic Alterations Cooperate with V-ha-ras to Accelerate Multistage Carcinogenesis in Tg.ac Transgenic Mouse Skin.
    Date August 1995
    Journal Cancer Research
    Excerpt

    TG.AC transgenic mice harbor a v-Ha-ras transgene and retain two normal c-Ha-ras alleles and are susceptible to skin tumor formation by 12-O-tetradecanoylphorbol-13-acetate (TPA). To determine whether normal c-Ha-ras antagonizes the oncogenic potential of the v-Ha-ras transgene and/or whether additional non-Ha-ras 7,12-dimethylbenz(a)anthracene (DMBA) initiation target genes exist in mouse skin, which could cooperate with v-Ha-ras to increase the frequency of initiation, rate of promotion, or risk of malignant conversion, we treated TG.AC mouse skin with a single subthreshold dose of DMBA. This was followed by limited TPA or diacylglycerol promotion to select for cells with additional genetic alterations over those cells containing the v-Ha-ras transgene only. DMBA-treated/TPA-promoted TG.AC mice demonstrated a 10-fold increase in the average number of papillomas per mouse, a greater incidence of papilloma bearing-mice, and an increased papilloma growth rate when compared to acetone-treated/TPA-promoted TG.AC mice. These profound changes in papilloma frequency and growth occurred in the absence of the characteristic DMBA-induced A182-->T mutation in c-Ha-ras and immunohistochemical nuclear staining for p53 protein. DMBA-treated/acetone-promoted TG.AC mice did not develop any tumors. Limited promotion with the model diacylglycerol, sn-1,2-didecanoylglycerol, similarly produced an average of 10-fold more papillomas in DMBA-treated mice than in acetone-treated/sn-1,2-didecanoylglycerol-promoted TG.AC mice. DMBA-treated/TPA-promoted TG.AC mice developed their first malignancy by 16 weeks, and by 30 weeks, 50% of the mice developed malignancies, whereas no malignancies were observed in acetone-treated/TPA-promoted TG.AC mice. These results indicate that there exist unidentified DMBA initiation target genes in TG.AC mouse skin that cooperate with mutant Ha-ras to increase papilloma frequency, growth, and malignant conversion, and that promoter treatment can influence malignant conversion by selecting for cells with multiple genetic alterations.

    Title The Irritable Bowel Syndrome: Long-term Prognosis and the Physician-patient Interaction.
    Date January 1995
    Journal Annals of Internal Medicine
    Excerpt

    OBJECTIVE: To evaluate the long-term course and prognosis associated with the irritable bowel syndrome (IBS) and to determine the influence of an effective physician-patient relationship on subsequent health care use. DESIGN: Prospective review of medical records. SETTING: Tertiary referral center. PATIENTS: 112 consecutive Olmsted County, Minnesota, residents who were first diagnosed with IBS at the Mayo Clinic during the period 1961-1963. RESULTS: The median follow-up was 29 years (range, 1 to 32 years) and patients made a median of 2 return visits for IBS-related symptoms (range, 0 to 12 visits). In addition to abdominal pain, diarrhea (reported by 50% of patients) was the predominant bowel symptom at diagnosis. Organic gastrointestinal disease occurred in 10 patients a median of 15 years after diagnosis of IBS. Survival in patients with IBS did not differ from expected survival (27 deaths; median survival > 30 years after initial diagnosis). A positive physician-patient interaction, defined a priori using objective criteria in the written record, was associated with fewer return visits for IBS. Of the eight variables examined, notations in the medical record about psychosocial history, precipitating factors, and discussion of diagnosis and treatment with patients were associated with fewer return visits for IBS-related symptoms. CONCLUSIONS: When diagnosed according to current criteria, IBS is associated with a good prognosis and the diagnosis is unlikely to be changed to that of an organic disease during follow-up. A positive physician-patient interaction may be related to reduced use of ambulatory health services by patients with IBS.

    Title The Skin: a Home to Multiple Classes of Epithelial Progenitor Cells.
    Date
    Journal Stem Cell Reviews
    Excerpt

    To maintain homeostasis in the adult skin, epithelial keratinocyte stem cells are thought to divide infrequently giving rise to short-lived (transit amplifying) cells that undergo a limited number of cell divisions and ultimately terminal differentiation. This model for the epidermal stem cell niche has increased in complexity by the multiple putative progenitor keratinocyte populations that have recently been identified in distinct regions of the interfollicular epidermis and hair follicle appendages. Under normal conditions, these progenitor populations are long-lived and able to sustain the cellular input to certain epidermal structures including the interfollicular epidermis and sebaceous gland. Other putative epithelial progenitors derived from the hair follicle possess high in vitro proliferative capacity and are able to regenerate skin, hair and sebaceous lineages in transplantation studies. These new findings present the cutaneous epithelium as a highly compartmentalized structure potentially maintained by multiple classes of progenitor cells. In this review, we will discuss the implications of these new putative epithelial progenitor populations and their potential to be influenced by external stimuli for skin homeostasis and carcinogenesis.

    Title Conditional Activin Receptor Type Ib (acvr1b) Knockout Mice Reveal Hair Loss Abnormality.
    Date
    Journal The Journal of Investigative Dermatology
    Excerpt

    The in vivo functions of the activin A receptor type 1b (Acvr1b) have been difficult to study because Acvr1b(-/-) mice die during embryogenesis. To investigate the roles of Acvr1b in the epithelial tissues, we created mice with a conditional disruption of Acvr1b (Acvr1b(flox/flox)) and crossed them with K14-Cre mice. Acvr1b(flox/flox); K14-Cre mice displayed various degrees of hairlessness at postnatal day 5, and the phenotype is exacerbated by age. Histological analyses showed that those hair follicles that developed during morphogenesis were later disrupted by delays in hair cycle reentry. Failure in cycling of the hair follicles and regrowth of the hair shaft and the inner root sheath resulted in subsequent severe hair loss. Apart from previous reports of other members of the transforming growth factor-β/activin/bone morphogenic protein pathways, we demonstrate a specialized role for Acvr1b in hair cycling in addition to hair follicle development. Acvr1b(flox/flox); K14-Cre mice also had a thicker epidermis than did wild-type mice, which resulted from persistent proliferation of skin epithelial cells; however, no tumor formation was observed by 18 months of age. Our analysis of this Acvr1b knockout mouse line provides direct genetic evidence that Acvr1b signaling is required for both hair follicle development and cycling.Journal of Investigative Dermatology advance online publication, 30 December 2010; doi:10.1038/jid.2010.400.


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