Biomedical subjects

I Arany

Publications and source records attributed to I Arany.

At least 19 recordsLinked to original sources

PubMed2006

STAT3 attenuates EGFR-mediated ERK activation and cell survival during oxidant stress in mouse proximal tubular cells.

We have shown that renal epithelial cell survival depends on the sustained activation of the extracellular signal-regulated protein kinase (ERK) and lack of this activation was associated with death during oxidative stress. ERK is activated via the canonical epidermal growth factor receptor (EGFR)-Ras-MEK pathway, which could be attenuated by oxidants. We now show that the failure to activate ERK in a sustained manner during severe oxidative stress is owing to the activation of the signal transducer and activator of transcription-3 (STAT3) rather than the failure to activate the EGFR. Tyrosine phosphorylation of the EGFR and STAT3 was studied in hydrogen peroxide (H(2)O(2))-treated mouse proximal tubule (TKPTS) cells or in mouse kidney after ischemia/reperfusion (I/R) injury by Western blotting. STAT3 activation was inhibited by either pharmacologically (AG490) through its upstream janus kinase (JAK2) or by a dominant-negative STAT3 adenovirus. EGFR was inhibited by AG1478. Survival was determined by fluorescence-activated cell sorter analysis and trypan blue exclusion. We found that the EGFR was phosphorylated on its major autophosphorylation site (Tyr1173) regardless of the H(2)O(2) dose. On the other hand, both I/R and severe oxidative stress - but not moderate stress - increased tyrosine phosphorylation of STAT3 in an EGFR and JAK2-dependent manner. Inhibition of JAK2 or STAT3 lead to increased ERK activation and survival of TKPTS cells during severe oxidative stress. Our data suggest a role of tyrosine-phosphorylated STAT3 in the suppression of ERK activation. These data suggest that the STAT3 pathway might represent a new target for improved survival of proximal tubule cells exposed to severe oxidant injury.

Animals↗

PubMed2001

Human papillomavirus, smoking, and cancer.

BACKGROUND: The effect of smoking on human papillomavirus (HPV) activity and subsequent dysplasia and neoplasia remains controversial. OBJECTIVE: To determine any reported effects of smoking on either HPV activity or HPV-related dysplasia/cancer using retrospective analysis of the literature from 1966 through 1998 via Toxline and PubMed to search for "smoking," "papillomavirus," and "cancer." CONCLUSION: Several recent large studies demonstrated that smoking was associated with a greater incidence of cervical, vulvar, penile, anal, oral, and head and neck cancer in a dose-dependent fashion, while other studies did not show any correlation between smoking and cervical dysplasia after multivariate adjustment. Recent studies have also indicated that smoking may be more closely related to high-grade lesions of the cervix and vulva. These data provide evidence of an association between HPV, smoking, and cancer. Progression of dysplasia likewise seems to be associated with smoking. Several groups have attempted to discern whether the connection between smoking and cervical cancer is from local immunosuppression and/or from direct carcinogenic effects.

Anus Neoplasms↗

PubMed2001

Verrucous carcinoma of the foot associated with human papillomavirus type 16.

BACKGROUND: We present 2 patients with verrucous carcinoma (VC) of the foot, a malignancy of unknown origin. OBJECTIVE: Molecular studies from the VCs were undertaken to determine the presence, type, and physical state of human papillomavirus (HPV) as well as the expression levels of certain oncogenes and antioncogenes. METHODS: Synthetic consensus and type-specific primers were used to determine the HPV type from both VCs via polymerase chain reaction (PCR). Verification of fragments was accomplished by means of specific isotope-labeled oligonucleotide probes. The physical state of HPV DNA was determined by two-dimensional gel electrophoresis. Quantitative oncogene and antioncogene expression studies were performed with the use of reverse transcriptase PCR. RESULTS: HPV type 16 was identified in episomal and integrated forms in both tumors. Expression studies revealed increased messenger RNA levels of c-Ki-ras oncogene and the p53 antioncogene and decreased messenger RNA levels of the Rb antioncogene in both VCs. CONCLUSION: Episomal and integrated forms of HPV-16 DNA were found in VCs of the foot, along with alterations of c-Ki-ras, p53, and Rb genes.

Carcinoma, Verrucous↗

PubMed2001

The endogenous interferon system in anal squamous epithelial lesions with different grades from HIV-positive individuals.

Anal intraepithelial lesions (ASILs) are considered as precursors of anal cancer. The incidence of high-grade ASIL (HSIL) and progression of low-grade ASIL (LSIL) to HSIL are high in HIV-positive men. Endogenous cytokines, such as interferons (IFNs) play an important role in the regulation of proliferation and immune responses in epithelial cells, and thus, they might control the above-mentioned progression events. Accordingly, we determined mRNA levels of IFN-gamma and IFN-gamma receptors, levels of IFN-gamma receptor-associated kinases (JAK1 and TYK2) and signalling molecules (signal transducer and activator of transcription-1 [STAT1], STAT3, interferon-responsive-factor-1 [IRF-1] and IRF-2) as well as inhibitors of cytokine signalling (protein inhibitor of activated STAT1 [PIAS1] and suppressor of cytokine signalling 2 [SOCS2]) in biopsies of anal condylomas, LSILs as well as HSILs from HIV-positive individuals by a semi-quantitative reverse transcribed polymerase chain reaction (RT-PCR) method. We found that HSIL significantly differs in expression of these genes from LSIL and condylomas. Expression profile of HSIL samples showed activation of STAT3 signalling, probably accounting for the observed high levels of genes that support cellular proliferation (IRF-2, c-fos and c-myc). Decreases in levels of suppressors (IFN-gamma and IRF-1) and JAK1 kinase, but increases in levels of inhibitors of cytokine signalling (PIAS1 and SOCS2) might also contribute to the altered cytokine signalling in HSIL biopsies. These findings might reveal important molecular events associated with progression of LSIL to HSIL in HIV-infected men.

Anal Canal↗

PubMed2001

Clinical and molecular responses in high-grade intraepithelial neoplasia treated with topical imiquimod 5%.

OBJECTIVE: To assess the clinical and molecular response of patients with recurrent high-grade vulvar, vaginal, or cervical intraepithelial neoplasia treated with topical 1-2(2-methylpropyl)-1H-imidazo [4,5-c] quinolin-4-amine (imiquimod) cream 5%, an immune response modifier with known efficacy in the treatment of external genital warts. METHODS: This is the first case series in the peer-reviewed literature reporting the use of imiquimod in high-grade intraepithelial neoplasia of the lower genital tract. Eight patients with high-grade intraepithelial neoplasia were treated with imiquimod in the gynecological oncology clinic and the HIV gynecology clinic at The University of Texas Medical Branch at Galveston. Frozen biopsies were available for RNA extraction on four patients before and after therapy. Using semiquantitative reverse transcription-PCR, we measured RNA levels of IFNs alpha and gamma, 2',5'-oligoadenylate synthetase, as well as CD4 and CD8 lymphocyte markers. RESULTS: Of the patients treated, four had complete responses, two had partial responses, one progressed, and one did not tolerate the therapy. Of the four complete responders, two remained disease-free (mean follow-up, 33 months). 2',5'-Oligoadenylate synthetase RNA expression showed an increased trend after therapy. CONCLUSIONS: These results obtained in this small and heterogeneous group merit further study in the use of topical 5% imiquimod use in the treatment of intraepithelial neoplasia. An important mechanism of action of imiquimod may involve 2',5'-oligoadenylate synthetase antiviral activity.

2',5'-Oligoadenylate Synthetase↗

PubMed2000

Response of keratinocytes from normal and psoriatic epidermis to interferon-gamma differs in the expression of zinc-alpha(2)-glycoprotein and cathepsin D.

Psoriasis is a T cell-mediated inflammatory disease characterized by hyperproliferation and by aberrant differentiation. We found cathepsin D and zinc-alpha(2)-glycoprotein, two catalytic enzymes associated with apoptosis and desquamation, to be present in the stratum corneum of the normal epidermis but absent from the psoriatic plaque. Psoriasis is characterized by an altered response to interferon-gamma (IFN-gamma), including the induction of apoptosis in normal but not in psoriatic keratinocytes, often with opposite effects on gene expression of suprabasal proteins. We found that IFN-gamma binding and signaling were attenuated in psoriasis: The IFN-gamma receptor, the signal transducer and activator of transcription STAT-1, and the interferon regulatory factor IRF-1 were strongly up-regulated by IFN-gamma in normal keratinocytes, but not in psoriatic ones. IFN-gamma strongly up-regulated the expression of the catalytic enzymes cathepsin D and zinc-alpha(2)-glycoprotein in normal keratinocytes but down-regulated them in psoriatic ones; the reverse was true of the apoptotic suppressor bcl-2. We believe that the aberrant response to IFN-gamma plays a central role in the pathophysiology of psoriasis, particularly the disruption of apoptosis and desquamation.

Cathepsin D↗

PubMed2000

Correlation between pretreatment levels of interferon response genes and clinical responses to an immune response modifier (Imiquimod) in genital warts.

Imiquimod (IQ) has been successfully used in treatment of genital warts. In clinical settings, patients responded well but wart reduction rates varied. Our aim was to find a correlation between clinical responses and pretreatment (constitutive) levels of genes that might be involved in the molecular action of IQ. Since IQ is a cytokine inducer, we analyzed levels of expression of genes of the JAK/STAT signaling pathway and their inhibitors as well as interferon response factors (IRFs) in pretreatment biopsy specimens from complete responders (99 to 100% wart reduction rate) versus incomplete responders (75 to 92% wart reduction rate) by reverse transcription-PCR. We found that mRNA levels of signal transducer and activator of transcription 1 (STAT1) and IRF1 were higher in complete responders than in incomplete responders. Incomplete responders expressed larger amounts of STAT3, IRF2, and protein inhibitor of activated STAT1 (PIAS1) mRNAs compared to complete responders before IQ treatment. We hypothesize that high-level expression of STAT1 and IRF1 is advantageous for a better IQ response. The observed differences in constitutive mRNA levels of these genes may be the consequence of alterations in cellular differentiation and/or variable expression of endogenous interferons. Previous in vitro studies showed that keratinocyte differentiation coordinates the balance between positive and negative signals along the JAK/STAT pathway by regulating the IRF1:IRF2 and STAT1:PIAS1 ratios and thus affecting induction of IQ-inducible genes. Specifically, differentiation supports constitutive expression of STAT1 and IRF1 mRNAs but not expression of IRF2 and PIAS1. Our data are in good agreement with studies that showed the importance of STAT1 in cytokine induction and activation of interferon-responsive genes by IQ.

Aminoquinolines↗

PubMed1999

Characterization of zinc-alpha(2)-glycoprotein as a cell adhesion molecule that inhibits the proliferation of an oral tumor cell line.

Zn-alpha(2)-glycoprotein (Znalpha(2)gp) is a soluble protein widely distributed in body fluids and glandular epithelia. We have found it to be expressed in stratified epithelia as well. Znalpha(2)gp is clinically correlated with differentiation in various epithelial tumors, including oral and epidermal tumors. We have cloned epidermal Znalpha(2)gp and report the preparation of the recombinant protein in a Baculovirus expression system. Like the native molecule, recombinant Znalpha(2)gp has RNase activity. Znalpha(2)gp functions as a matrix protein for the Tu-138 oral squamous cell carcinoma cell line. Cell attachment to Znalpha(2)gp is comparable to that for fibronectin and is inhibited by the synthetic RGD peptides RGD, RGDV, and RGDS. Attachment is also inhibited by the antibody to integrin alpha(5)beta(1) (the fibronectin receptor), but not by antibodies to integrins alpha(v)beta(3), alpha(3)beta(1), and alpha(2)beta(1). We find that the proliferation of Tu-138 cells is inhibited on a Znalpha(2)gp matrix, as compared with other matrix proteins (fibronectin, vitronectin, laminin, and collagens I and IV) on which growth resembles that on the BSA control. We believe that the role of Znalpha(2)gp in differentiation and its RNase activity are two likely suspects as agents of the inhibition of proliferation.

Antibodies↗

PubMed1999

Zinc-alpha2-glycoprotein expression as a marker of differentiation in human oral tumors.

Zinc-alpha2-glycoprotein (Znalpha2gp) is a soluble major histocompatibility complex homolog widespread in body fluids and in glandular epithelia; the authors recently demonstrated its presence in stratified epithelia. Znalpha2gp has been associated with tumor differentiation in breast cancers and other carcinomas. We compare here its gene expression in histopathologically graded oral squamous cell carcinomas and in their perilesional normals. Znalpha2gp levels are higher in the controls than in the tumors, and higher in well-differentiated tumors than in poorly differentiated ones. Markers of oral epithelial maturation (keratin K13 and involucrin) are less simply related to tumor histology.

Biomarkers, Tumor↗

PubMed1999

Enhancement of the innate and cellular immune response in patients with genital warts treated with topical imiquimod cream 5%.

The mechanism of action of imiquimod 5% cream applied topically to patients with genital warts was evaluated in a double-blind, placebo-controlled study. Imiquimod (16 patients) or placebo (three patients) was applied three times per week for up to 16 weeks. All imiquimod-treated patients had a > or =75% reduction in total wart area while only one of three placebo-treated patients had a similar reduction. Wart biopsies were taken at prestudy, week 6, and end of treatment. Polymerase chain reaction (PCR) for human papillomavirus (HPV) DNA and reverse transcriptase (RT)-PCR for messenger (m)RNAs were used to identify cytokines, cellular markers, viral gene products, and cell cycle markers in these biopsies. Treatment with imiquimod, an immune response modifier, stimulated significant increases in mRNA for interferon (IFN)-alpha, IFN-gamma and 2',5' oligoadenylate synthetase (2',5'-AS) as well as a tendency towards increases in tumor necrosis factor (TNF)-alpha and interleukin-12 p40. Significant increases in mRNA for CD4 and a trend toward increases in CD8 were also observed in imiquimod-treated patients, suggesting activation of a cell mediated immune response. Imiquimod administration was also associated with a significant decrease in viral load as measured by HPV DNA and L1 mRNA. The effects on HPV markers were accompanied by an apparent decrease in mRNA expression for markers of cell proliferation and an increase in mRNA for markers of keratinocyte differentiation and tumor suppressors.

Adolescent↗

PubMed1998

Zinc-alpha 2-glycoprotein has ribonuclease activity.

Zinc-alpha 2-glycoprotein (Zn alpha 2gp) is widely distributed in body fluids and in various epithelia; its gene has been completely sequenced, but its function has long remained elusive. We have found that Zn alpha 2gp has RNase activity, comparable to onconase but two orders of magnitude less than RNase A. The RNase activity of Zn alpha 2gp is characterized by maxima in pH at 7.5, in ionic strength at 50 mM NaCl, and in temperature at 60 degreesC. It is strongly inhibited by ZnCl2, but unaffected by MgCl2. It is partially inactivated (down to 20%) by the placental RNase inhibitor. On synthetic polyribonucleotide substrates, the RNase activity of Zn alpha 2gp is specific for pyrimidine residues [poly(C) and poly(U) equally] and cleaves only single-stranded RNA. For onconase, it has been demonstrated that the RNase activity depends on pyroglutamic acid (pyr 1) as the N-terminus; Zn alpha 2gp also has pyr 1, while RNase A does not. Alignment of the amino acid sequences of Zn alpha 2gp and onconase or RNase A reveals only modest matches. Despite the more substantial overall structural homology of Zn alpha 2gp to class I major histocompatibility complex proteins, Zn alpha 2gp has not been proven to be associated with the immune response and, conversely, we could not detect RNase activity in six class I HLA heavy chains.

Enzyme Activation↗

PubMed1998

Mechanism of action of imiquimod 5% cream in the treatment of anogenital warts.

Objective: The objective of this randomized, double-blind, placebo-controlled trial was to evaluate the mechanism of action of imiquimod cream in the treatment of anogenital warts, and to apply the findings to the results of previously conducted safety and efficacy trials.Methods: Imiquimod (16 patients) or placebo (3 patients) cream was applied 3 times a week for up to 16 weeks; cream remained on the skin overnight for 8 +/- 2 hours. Wart biopsies were taken at prestudy, week 6, and the end of treatment (just prior to clearance or at week 16) and analyzed using PCR for HPV/DNA and RT-PCR for mRNA to identify cytokines, cellular markers, markers of proliferation and differentiation, and viral gene products. Efficacy was assessed based on wart area regression as documented by wart area measurements and photographs.Results: All patients enrolled in the trial had HPV type 6/11. All imiquimod-treated patients experienced a >/=75% clearance in baseline/target wart area. Imiquimod treatment stimulated significant increases in mRNA for IFN-alpha, 2'5' AS and IFN-gamma. Increases in mRNA for CD4, CD8, and TNF-alpha were also observed, suggesting activation of a T-helper type-1 cell mediated response. During the trial one of the vehicle treated patients also experienced spontaneous wart clearance; comparisons of the cytokine levels for this patient were similar to those observed for the imiquimod treated patients.Conclusions: The results of this mechanism of action trial indicate that the stimulation of local cytokines and cellular infiltrates by imiquimod leads to a reduction of HPV types 6 and 11 viral load with subsequent wart regression and normalization of keratinocyte proliferation without evidence of scarring. In two previous randomized vehicle-controlled trials evaluating patients with anogenital warts, the majority of patients had HPV-DNA types 6 or 11 as assessed by in situ hybridization. These results provide additional insight into the mechanism of total clearance for these otherwise healthy patients. The Th1 response demonstrated in this trial also explains the lower total clearance rates demonstrated in HIV-positive and AIDS patients.

Journal Article↗

PubMed1998

Tumor differentiation-dependent local immunity in human head and neck cancers.

Distribution of markers of local cell-mediated immunity was examined in oral tumors exhibiting different histological stages of differentiation. Using a RT-PCR-based semiquantitative technique we determined levels of Langerhans cells, CD4- and CD8-positive T-cells, macrophages/NK cells, beta2-microglobulin and IFN-gamma mRNAs from tissue biopsies. A positive correlation was found between levels of these immunological markers and the tumor differentiation stage. Since tumor differentiation may correlate with the prognosis and response to various treatment modalities, our results may be useful clinically.

Antigens, CD1↗

PubMed1998

Induction by interferon-gamma of its receptor varies with epithelial differentiation and cell type.

Normal keratinocytes from epidermis and from buccal mucosa were cultured to confluence in three media with graded differentiation potential and treated with interferon-gamma (IFN-gamma). RT-PCR was used to measure the gene expression of the IFN-gamma receptor (IFNGR-1), as well as the immunomodulator HLA-DR and two enzymes of the 2-5 A pathway. We have previously reported results for a number of structural and regulatory genes in the same system (and include here involucrin for comparison). In epidermal keratinocytes, the induction of IFNGR-1 was upregulated by incubation with IFN-gamma, and this increased with the differentiation potential of the culture medium. A roughly similar pattern occurred for the other genes. In mucosal keratinocytes, in contrast, IFN-gamma failed to induce expression of IFNGR-1 or the other genes. A unique characteristic of HLA-DR was that its induction by IFN-gamma was uniform, for both tissues and all media. The gene expression of the receptor IFNGR-1 appears to be the dominant factor in the sensitivity of other genes to IFN-gamma, although there are substantial disparities among them that presumably reflect functional differences. The difference between the two tissues may be linked to differentiation, as the epidermis has a much more extensive maturation pattern than the buccal mucosa. A clinical implication is a better prognosis for IFN-gamma treatment for more differentiated tumors. Indeed, a previous study has found that the maturation pattern of condylomas responding to interferon treatment resembles that of epidermis, whereas the maturation of nonresponders is more akin to that of buccal mucosa.

2',5'-Oligoadenylate Synthetase↗

PubMed1998

Isoforms of cathepsin D and human epidermal differentiation.

Cathepsin D is an ubiquitously expressed lysosomal aspartic proteinase, with well-determined structural and chemical properties but a less clearly defined biological role. In stratified epithelia, the chronology of cathepsin D activation and degradation can be connected with stages of cellular differentiation. We partially purified cathepsin D from human epidermis and from separated stratum corneum by standard biochemical procedures, monitored by SDS-PAGE and Western blotting, and verified its identity as to molecular mass, pH optimum, N-terminal sequencing, reactivity with the specific antibody, inhibition by pepstatin A, and specific enzyme activity. It had hemoglobin-degrading activity over the acid range, with maximum at pH 3. It also degraded bovine serum albumin, human keratins, and stratum corneum extracts at pH 4. We discerned all three isoforms of human cathepsin D (the 52 kDa proenzyme and the active forms at 48 kDa and 33 kDa) in the epidermis; both active forms were also seen in the stratum corneum, but the proenzyme was not. Gene expression of cathepsin D in epidermal keratinocytes resembled that of suprabasal structural proteins (involucrin, keratin K10, transglutaminase) in its response to the calcium switch. An antibody to the 33 kda isoform immunolocalized to the granular layer and the stratum corneum (whereas antibodies to the 48 kDa isoform have been reported to stain mainly the upper spinous and granular layers). A plausible hypothesis to harmonize these results is that cathepsin D is first expressed as the proenzyme in the upper spinous layer, is activated in the lysosomes in the granular layer to the 48 kDa form, and is degraded to the 33 kDa form in the transition zone between the granular layer and the stratum corneum. As the stratum corneum is an acid environment, with an ambient pH of approximately 4.5, cathepsin D is available and suited to contribute to desquamation.

Amino Acid Sequence↗

PubMed1998

A randomized, controlled, molecular study of condylomata acuminata clearance during treatment with imiquimod.

Imiquimod, an immune response modifier, has been demonstrated to be safe and effective in the treatment of external genital and perianal warts caused by human papillomavirus (HPV). To identify the molecular mechanism(s) by which condylomata acuminata clear during topical treatment with imiquimod, wart skin biopsies were taken from patients before treatment, at treatment week 6, and at the end of treatment. Tissues were analyzed for HPV DNA and for mRNA of several cytokines and HPV gene products. Wart clearance was associated with evidence of tissue production of interferon-alpha, -beta, and -gamma and tumor necrosis factor-alpha. Regression of warts was strongly associated with a decrease in HPV DNA and in mRNA expression for both early and late viral proteins. Thus, topical imiquimod treatment of anogenital warts led to significant increases in local production of multiple interferon mRNAs and a significant reduction in virus load as measured by decreases in HPV DNA and mRNA for early HPV proteins.

Administration, Topical↗

PubMed1998

Combined Epstein-Barr virus and human papillomavirus infection in nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) has been shown to be a likely etiologic agent in nasopharyngeal carcinogenesis. Human papillomaviruses (HPVs) have previously been identified in numerous upper aerodigestive tract carcinomas. This pilot study was undertaken to investigate the prevalence of combined EBV and HPV infection in 17 patients with nasopharyngeal carcinoma (NPCA) using polymerase chain reaction (PCR). The primary goal was to determine if the presence of HPV could be correlated with molecular, histologic, or clinical parameters. There were seven patients with undifferentiated NPCA (World Health Organization [WHO] type III) and 10 patients with squamous cell carcinoma (WHO type I). All 17 patients had stage IV disease at presentation. EBV was identified in 15 patients (88.2%), and HPV subtypes were identified in samples from nine patients (52.9%). All HPV-positive cases were also EBV positive. Western blot analysis of six samples showed a high level of expression of c-myc and cdc2 kinase and a low level of p53 protein in NPCAs that contained both HPV and EBV (n = 3). Increased expression of c-myc and cdc2 kinase was seen in the cases that contained EBV only, but to a lesser extent (n = 2). These findings indicate an effect of the virus on cellular proliferation and differentiation. Similarly, an elevated level of Rb protein was found only in the HPV-containing NPCAs. Moderate differentiation (keratinization) occurred in four of eight HPV-negative and none of the nine HPV-positive NPCAs. (All HPV-positive cases were poorly differentiated or undifferentiated.) This difference is statistically significant for this sample size (P < 0.03). There was a trend for the group that was HPV positive to have WHO III histology and for the HPV-negative group to have WHO I. The presence of HPV could not be correlated with any clinical parameters in this small group of patients with advanced disease; however, these data suggest that coexistence of EBV and HPV infection may be a factor in the pathogenesis of NPCA and may have an effect on regulation of cellular proliferation and differentiation.

Adolescent↗

PubMed1998

Differentiation and cathepsin D expression in human oral tumors.

OBJECTIVES/HYPOTHESIS: This study aimed to ascertain whether cathepsin D expression could be related to the stage of differentiation of oral tumors. STUDY DESIGN: Human oral biopsies of 10 squamous cell carcinomas and of the corresponding perilesional normal tissues were used. The tumors had all been clinically graded as advanced stage but nonmetastatic; five were classified histopathologically as poorly differentiated. METHODS: The gene expression of cathepsin D and keratin K13 in the biopsies was measured by reverse transcription polymerase chain reaction. Ratios of tumor-to-control readings helped compensate for sample variability. RESULTS: Keratin K13, as a suprabasal cell marker, tended to confirm the histological grading of the tumors (but was not otherwise useful in distinguishing tumors from normal tissue). Substantial overexpression of cathepsin D was found in the poorly differentiated tumors. CONCLUSIONS: Cathepsin D overexpression is considered a prognostic indicator of metastasis. In this sample, it was also associated with dedifferentiation. Cathepsin D might serve as a valuable gauge in clinical exploration of the connection between dedifferentiation and metastasis.

Adult↗