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PubMed2006

Albumin stimulation of eosinophil migration involves PI3-kinases and is associated with diminished eosinophil CD49d and CD49f expression.

BACKGROUND: Albumin is known to induce chemokinesis and facilitate chemotaxis of human granulocytes in the Boyden chamber assay, but its mechanisms of action remain obscure. We have previously found that IL-2 inhibits albumin-stimulated eosinophil migration. The aim of this study was to identify the mechanisms behind the effects of albumin and IL-2 on the migration of human eosinophils. METHODS: Purified eosinophils were preincubated with inhibitors of signal transduction molecules before incubation with or without albumin and IL-2. The migration assay was performed in a 48-well microchemotaxis chamber. The effect of albumin and IL-2 on cell size and on the surface expression of adhesion molecules was studied with flow cytometry. RESULTS: Albumin-stimulated migration was inhibited by the PI3-kinase inhibitors wortmannin and LY-294002, but not by the PKC inhibitor RO-31-8220. IL-2 had no effect after preincubation with wortmannin or LY-294002. In contrast, the inhibitory effect of IL-2 remained after preincubation with RO-31-8220. Albumin increased the cell size as measured by forward scatter, and the expression of CD49d and CD49f decreased after incubation with albumin. IL-2 affected neither the expression of adhesion molecules nor the forward scatter. CONCLUSIONS: The stimulation of eosinophil migration by albumin is mediated by PI3-kinase, and the increase in cell size caused by albumin indicates activation of the cells. Decreased expression of CD49d and CD49f by albumin may diminish the adhesiveness of the cells, which in turn may facilitate migration. These are novel findings that indicate an active role for albumin in eosinophil migration.

Adult↗
PubMed1998

Detection of antigens by immunofluorescence on ultrathin cryosections of skin.

Cryoultramicrotomy was originally established to provide ultrathin cryosections as substrates for on-section immunolabeling in immunoelectron microscopy. Recently, we recognized that ultrathin cryosections of skin (0.2 micrometer thick) could serve as substrates for immunofluorescence (IF) with excellent resolution. To assess the advantages and the limitations of IF on ultrathin cryosections, we compared the labeling of IF on 0.2-micrometer ultrathin cryosections of skin with those of routine IF on 6-micrometer cryostat sections, confocal laser scanning microscopy (LSM), and immunogold electron microscopy using several markers of keratinocyte cell surface and basement membrane zone molecules. IF on ultrathin cryosections clearly demonstrated a lack of bullous pemphigoid antigens beneath the melanocytes, desmosomal antigens as discontinuous dot-like labeling, and nondesmosomal plasma membrane antigen as a ladder-like pattern. IF on ultrathin cryosections provided convincing images with higher resolution than confocal LSM, which corresponded well to those of immunogold electron microscopy. IF on ultrathin cryosections had superior resolution compared to routine IF or confocal LSM and should serve as a powerful tool in future studies for the analysis of skin antigens. (J Histochem Cytochem 46:1455-1460, 1998)

Antigens, CD↗
PubMed1996

Insulin-like growth factor-I stimulates neurogenesis in chick retina by regulating expression of the alpha 6 integrin subunit.

Insulin-like growth factor I (IGF-I) strongly stimulates the generation of differentiated neurons in cultures of neuroepithelial cells of the embryonic chick neural retina in the presence of a laminin-1 tissue culture substrate. Treatment of cultured neuroepithelial cells with IGF-I rapidly up-regulated the mRNA coding for the alpha 6 integrin subunit whereas specific reduction of alpha 6 subunit levels by treatment with an alpha 6 integrin antisense oligonucleotide resulted in reduced neuronal differentiation in vitro. Although IGF-I immunoreactivity is seen throughout the neural retina, expression of IGF-I mRNA is confined to the pigment epithelium during the period of neurogenesis in vivo. Neutralization of the endogenous IGF-I with a blocking antibody down-regulated levels of alpha 6 integrin mRNA and reduced the production of differentiated retinal neurons in vivo. These data indicate a role for IGF-I in the generation of retinal neurons mediated by the interaction of laminin with its alpha 6 integrin subunit-containing receptor.

Animals↗
PubMed1996

Integrin alpha 6 expression is required for early nervous system development in Xenopus laevis.

The integrin alpha 6 subunit pairs with both the beta 1 and beta 4 subunits to form a subfamily of laminin receptors. Here we report the cDNA cloning and primary sequence for the Xenopus homologue of the mammalian integrin alpha 6 subunit. We present data demonstrating the spatial and temporal expression of alpha 6 mRNA and protein during early development. Initially, alpha 6 transcripts are expressed in the dorsal ectoderm and future neural plate at the end of gastrulation. Later in development, alpha 6 mRNAs are expressed in a variety of neural derivatives, including the developing sensory placodes (otic and olfactory) and commissural neurons within the neural tube. Integrin alpha 6 is also expressed in the elongating pronephric duct as well as a subset of the rhombencephalic neural crest, which will form the Schwann cells lining several cranial nerves (VII, VIII and X). In vivo expression of an alpha 6 antisense transcript in the animal hemisphere leads to a reduction in alpha 6 protein expression, a loss of adhesion to laminin, and severe defects in normal development. In 35% of cases, reduced levels of alpha 6 expression result in embryos that complete gastrulation normally but arrest at neurulation prior to the formation of the neural plate. In an additional 22% of cases, embryos develop with severe axial defects, including complete loss of head or tail structures. In contrast, overexpression of the alpha 6 subunit by injection of full-length mRNA has no apparent effect on embryonic development. Co-injection of antisense and sense plasmid constructs results in a partial rescue of the antisense-generated phenotypes. These data indicate that the integrin alpha 6 subunit is critical for the early development of the nervous system in amphibians.

3T3 Cells↗
PubMed2003

Differential regulation of cell adhesive functions by integrin alpha subunit cytoplasmic tails in vivo.

Cell adhesion to fibronectin (FN) is crucial for early vertebrate morphogenesis. In Xenopus gastrulae, several distinct integrin-dependent adhesive behaviors can be identified: adhesion of cells to FN, assembly of FN fibrils, and initiation of cell spreading and migration in response to mesoderm inducing signals. We have taken a chimeric integrin approach to investigate the role of the integrin alpha cytoplasmic tail in the specification of these developmentally significant adhesive functions. Cytoplasmic tail-deleted alpha4 constructs and alpha4-ectodomain/alpha-cytoplasmic tail chimeras were generated and expressed in whole embryos. Normal gastrula cells lack integrin alpha4 and, correspondingly, are unable to adhere to the alpha4 ligand, the V-region of FN. The ability of alpha4 constructs to promote adhesive behaviors was established by placing tissue explants or dissociated cells on an FN V-region fusion protein that lacks the RGD (Arg-Gly-Asp)/synergy sites or treating whole embryos with antibodies that block endogenous integrin-FN interactions. We found that each alpha4 cytoplasmic domain deletion mutant and alpha-tail chimera examined could support cell attachment; however, activin induction-dependent cell spreading, mesoderm cell and explant motility, and the ability to assemble FN matrix on the blastocoel roof varied with specific alpha subunit tail sequences. These data suggest that alpha cytoplasmic tail signaling and changes in integrin activation state can regulate a variety of developmentally significant adhesive behaviors in both space and time.

Activins↗
PubMed2006

Spatial and temporal control of laminin-332 (5) and -511 (10) expression during induction of anagen hair growth.

Basement membrane plays important roles in hair growth. We characterized changes in laminin isoform expression during hair cycling. At the mRNA level, laminin-511 (10) expression underwent a steady increase during anagen stages. In contrast, laminin-332 (5) expression was initially upregulated in outer root sheath (ORS) keratinocytes at anagen II and then transiently downregulated. Laminin-332 significantly increased coincident with the signal in inner root sheath and hair matrix cells after anagen IV. Levels of laminin-332 proteins were also upregulated at late anagen I-III but dropped after anagen IV. This decrease coincided with increased levels of mRNA encoding the two proteases, membrane type 1 metalloproteinase and bone morphogenetic protein 1, involved in laminin-332 processing. Immunohistochemistry demonstrated that laminin-332 and alpha6 beta4 integrin were well colocalized, but their signals were remarkably decreased in the lower half of follicles after anagen VI. Consistent with these data, ultrastructurally mature hemidesmosomes were seen in ORS keratinocytes at anagen II, whereas at anagen VI, only fragmental hemidesmosomes were present. In hair follicle culture, laminin-511 (10)/521 (11)-rich human placental laminin enhanced hair growth, whereas recombinant laminin-332 antagonized hair growth induced by laminin-511. Our results indicate a positive role for laminin-511 and a negative role for laminin-332 on hair growth.

Animals↗
PubMed2005

FACS enrichment of human keratinocyte stem cells.

Recent work from our laboratory has led to the development and validation of fluorescence-activated cell sorting (FACS)-based techniques to prospectively isolate viable keratinocyte stem cells from both human and murine skin. Here we describe a step-by-step method to apply our technique to isolate epidermal keratinocytes from skin tissue, process them for immunofluorescent staining for cell surface markers, and subject them to fluorescence-activated cell sorting to obtain the stem, transient amplifying, and early differentiating keratinocyte fractions. These viable cells can then be placed into culture for further analysis or directly into keratinocyte assays, such as organotypic cultures or in vivo transplantation. This method will be useful for the complete biological characterization of keratinocyte progenitors with respect to wound healing, carcinogenesis, and therapeutic manipulation.

Animals↗
PubMedDate not supplied

Laminin-5 beta3A expression in LNCaP human prostate carcinoma cells increases cell migration and tumorigenicity.

Interactions between extracellular matrix proteins and prostate carcinoma cells change dramatically during prostate tumor progression. We have concentrated on two key modifications that occur in the hemidesmosome in prostate carcinoma: loss of laminin-5 protein expression and altered basal cell polarity of the alpha6beta4 integrin. We previously demonstrated two cell line-specific isoforms (beta3A and beta3B) of the LAMB3 message. Cells expressing only the beta3B isoform did not translate the beta3 protein and were unable to assemble the laminin-5 trimer. One such cell line, LNCaP, was selected to determine whether restoration of the laminin-5 beta3A isoform would cause expression of a functional laminin-5 beta3 chain, assembly and secretion of the laminin-5 trimer, and reversion to a non-neoplastic phenotype. Laminin-5 beta3A cDNA was cloned and stably transfected into LNCaP cells. We observed the restoration of the beta3 protein, but a laminin-5 trimer was not secreted. Moreover, increased cell migration was demonstrated, and tumorigenicity was increased in SCID mice. A microarray analysis, performed between transfected and nontransfected LNCaP cells, showed most changing genes to be associated with signal transduction. The beta3 chain of laminin-5 may thus play an important role in signal transduction, which may enhance cell motility and tumorigenesis.

Animals↗
PubMed2006

Identification of candidate murine esophageal stem cells using a combination of cell kinetic studies and cell surface markers.

The identification and characterization of esophageal stem cells are critical to our understanding of the biology of the esophageal epithelium in health and disease. However, the proliferative compartment within the mouse esophageal epithelium remains poorly characterized. Here, we report that the basal cells of the mouse esophagus can be separated into three phenotypically and functionally distinct subpopulations based on the expression of alpha(6) integrin and transferrin receptor (CD71). Cells that express high levels of alpha(6) integrin and low levels of CD71, termed alpha(6)(bri)CD71(dim), are a minor subpopulation of small and undifferentiated cells that are enriched for label-retaining cells and thus represent a putative esophageal stem cell population. Conversely, cells expressing high levels of both alpha(6) integrin and CD71 (alpha(6)(bri)CD71(bri)), the majority of basal esophageal cells, are enriched for actively cycling cells and therefore represent a transit-amplifying population. Kinetic analyses revealed that a third cell population, which is alpha(6) integrin-dim and CD71-bright (alpha(6)(dim)), is destined to leave the basal layer and differentiate.

Animals↗
PubMed1995

Gradient of integrin alpha 6A distribution in the myocardium during early heart development.

The interactions of cells with extracellular matrices (ECM)1 are likely to be key determinants of embryonic development. Integrin adhesion receptors are ideally positioned to mediate some of these interactions since, in addition to mechanical adhesion, they transduce signals affecting cell proliferation and differentiation. We investigated expression of the integrin alpha 6 beta 1, a receptor for the ECM component, laminin in the early mouse embryo. An intriguing feature of this integrin is the existence of alpha 6 subunit isoforms. The A and B isoforms, which differ in the cytoplasmic tails, are expressed in cell-type specific fashion, and are likely to implement distinct cellular interactions with laminin. By RT-PCR, alpha 6B but not alpha 6A mRNA was detectable in embryo extracts from fertilized oocytes to 6.5 d.p.c. In subsequent stages, up to 11.5 d.p.c., alpha 6A mRNA was observed in mRNA extracts from whole embryos, but still in significantly lower amounts than alpha 6B. However, in extracts from isolated heart (9.5 to 11.5 d.p.c.), alpha 6A was the predominant alpha 6 isoform, while in extracts from other embryo parts no alpha 6A mRNA was detectable. At the protein level, immunostaining with specific antibodies showed alpha 6A protein in myocardial cells, at the early stage of heart tube development (8.5 d.p.c.). Localization to the myocardium was tightly restricted, since other structures of the embryonic heart, e.g., endocardium, or of the remaining embryo did not stain with anti-alpha 6A antibody. In the ventricular myocardium, expression of alpha 6A appeared more intense than in the subendocardial layer. Quantitation by confocal microscopy unveiled a gradient of expression of alpha 6A, increasing from the outer to the inner layers of the myocardium. This is the first demonstration of a gradient distribution of integrin molecules in a tissue, which appears to be directly connected with the process of organogenesis. The mechanism underlying our observations is not the turning on of a gene, rather it is the activation of a splicing mechanism that substitutes the cytoplasmic domain of a laminin receptor. Because integrin cytoplasmic domains are thought to be an important functional end of the molecule, this may be a mechanism to modulate cellular responses to laminin.

Animals↗
PubMed1995

An alternatively spliced exon in the extracellular domain of the human alpha 6 integrin subunit--functional analysis of the alpha 6 integrin variants.

Variants in the extracellular domain of the integrin alpha 7 subunit which arise as a consequence of alternative splicing of mRNA have recently been reported. Two alternative exons, X1 and X2, have been identified in the alpha 7 gene, and homologous exons were found for alpha 6 (Ziober et al., 1993). In this study, we have isolated the region of the alpha 6 gene containing exons X1 and X2 that are, like those of alpha 7, located between stretches of DNA that encode the homologous repeat domains III and IV, proximal to the three divalent cation binding sites of the alpha 6 subunit. We demonstrated by reverse transcriptase polymerase chain reactions and confirmed by sequencing that alpha 6X1 and alpha 6X1X2 mRNAs are generated by alternative splicing of exon X2. The alpha 6X1X2 mRNA is expressed in a limited number of tissues and cell lines and it is always co-expressed with the ubiquitous alpha 6X1 mRNA. Stable transfection of K562 cells with full length cDNAs for the alpha 6AX1X2 and beta 4 subunits resulted in cell populations that expressed the alpha 6AX1X2 variant, in association with either beta 1 or beta 4, on their surface. In addition, a population of cells was isolated that expressed the alpha 6AX1X2 variant at low levels and almost exclusively in association with beta 1. Comparison of the alpha 6AX1X2 integrins with alpha 6AX1 using similarly transfected cells showed no obvious differences between the alternative extracellular alpha 6A isoforms with respect to ligand specificity and activation-dependency of ligand binding. After treatment with the anti-beta 1 stimulatory antibody TS2/16, both the alpha 6AX1 beta 1 and alpha 6AX1X2 beta 1 integrin variants mediated cell adhesion to EHS tumor laminin (laminin-1), kalinin (laminin-5), human placental (laminin-2 and -4) and bovine kidney laminins. In contrast, the alpha 6AX1 beta 4 and alpha 6AX1X2 beta 4 integrins also mediated cell adhesion to laminin and kalinin without stimulation. Furthermore, the different transfectants did not differ in their ability to spread on kalinin. The presented data indicate that the X2 region in alpha 6 is not involved in defining ligand specificity or affinity.

Alternative Splicing↗
PubMed2001

The influence of stromal contraction in a wound model system on corneal epithelial stratification.

PURPOSE: The healing process of some corneal wounds involves closure by stromal contraction and the renewal of the stratified epithelium. In wound gape injury such stromal contraction occurs with epithelial stratification. In previous in vitro studies of noncontracted and contracted corneal fibroblast-seeded collagen gels (FSCGs) it was shown that initiation of wound contraction by the myofibroblast phenotype (present within the wounded stroma) was dependent on vitronectin and/or fibronectin. This study considers one aspect of the epithelial-stromal interaction that occurs during wounding. The stratification of corneal epithelial cells on noncontracted and contracted corneal FSCGs was compared. METHODS: Dissociated bovine corneal epithelial cells were seeded on noncontracted and contracted corneal FSCGs, and these assemblies were cultured for 7 days. The epithelium that formed was evaluated using laser confocal microscopy and immunohistochemical markers directed against cytokeratin 3, desmoplakin I and II, integrin alpha-6 subunit, laminin, and collagen VII. The characteristics of the epithelium were compared with stromal carriers comprised of dissociated bovine corneal epithelial cells seeded on intact stroma and basement membrane (stromal carrier biopsies). RESULTS: The stratified epithelium that developed on contracted corneal fibroblast-seeded collagen gels was similar to that formed on stromal carriers, whereas nonstratified epithelium formed on noncontracted FSCGs. CONCLUSIONS: These studies showed that the contracted state of fibroblast-seeded gels enhanced the development of well-organized, stratified corneal epithelium.

Animals↗
PubMed2001

[Integrin alpha-6 in cervix neck squamous cell carcinoma HPV 16/18 positive and negative].

In the present paper we study expression of alpha-6 integrin in normal paraepidermal epithelium, in CIN and in cervical invasive carcinoma HPV 16/18 positive and negative. The results suggest that alpha-6 integrin might be a marker for the evaluation of malignancy of squamous cell carcinoma. There is no correlation between the expression of alpha-6 integrin and the presence of HPV.

Antigens, CD↗
PubMed2001

[The coordinated expression of laminin and its integrin receptor in hepatic sinusoidal capillarization].

OBJECTIVE: To explore the expression of laminin and its integrin receptor alpha 6 in sinusoidal capillaration. METHODS: The rat hepatic fibrosis model was established by injection carbon tetrachloride subcutaneously. Liver sections were examined by scanning electron microscopy and special staining. Then expressions of laminin and integrin alpha 6 subunit were observed by immunohistochemistry and dot immuno-blotting. RESULTS: The pathologic character of hepatic fibrosis-sinusoidal capillaration was observed. Sinusoidal capillaration is characterized by defenestration of sinusoidal endothelial cells (SEC) and basement membrane forming and phenotype transformation. By immunohistochemistry staining. The deposition of laminin surrounding sinusoids according to fibrosis stage was 0, 1.92%, 6.02%, 9.68%, 14.14% respectively, statistically different from each other (P < 0.05). In normal rat no expression of integrin alpha 6 were observed in SEC membranes. When capillaration integrin alpha 6 was detected in a continuous pattern along the sinusoidal in accordance with laminin assembly. The content of integrin alpha 6 in fibrotic liver tissues were significantly higher than in normal liver tissues as measured by dot immuno-blotting (P < 0.05). CONCLUSIONS: During fibrogenesis laminin continuously accumulate in liver tissues and form basement membrane resulting in sinusoidal capillaration, meanwhile are company with induced expression of LN-binding-integrin alpha 6 on SEC membranes. These results suggest that coordinated expression of laminin and laminin-binding-integrin might be important in pathogenesis of sinusoidal capillaration and hepatic fibrosis.

Animals↗
PubMed2002

Androgen induction of in vitro prostate cell differentiation.

To better understand androgen action in normal prostate cells, we characterized the androgen growth response of an immortalized nontumorigenic rat prostate cell line called CA25 that had been stably transfected with androgen receptor (AR) cDNA. Surprisingly, we found that AR(+) CA25 cells grew slower in the presence of dihydrotestosterone (DHT), whereas the growth of AR(-) CA25 cells was not affected by the hormone. DHT-mediated growth inhibition of CA25 cells was not attributable to an increase in apoptosis but rather to a morphological conversion consistent with terminal differentiation. Specifically, we found that DHT treatment of CA25 cells resulted in a striking change in cell architecture, localization of desmoplakin to cell-cell boundaries, and an increase in alpha 6p integrin levels, a newly described marker of cell differentiation. Although no androgen-dependent changes were observed in the transcript levels of the mitochondrial aspartate aminotransferase or c-Myc genes by Northern blot analysis, RNA expression profiling of DHT-treated CA25 cells identified 282 genes of 1,018 that were continually expressed over a 48-h period. It was found that 63 of these genes were up-regulated >5-fold within the first 4 h of treatment and encoded functions involved in transport, signal transduction, and metabolism. These expression profile data are consistent with the striking morphological changes we observed in DHT-treated CA25 cells and provide a starting point for molecular analysis of in vitro prostate cell differentiation.

Animals↗
PubMed2002

[Expression of integrin alpha 6 in hepatic sinusoidal capillaration].

OBJECTIVE: To explore the expression of integrin alpha 6 in hepatic sinusoidal capillaration. METHODS: The rat hepatic fibrosis model was established by injection of carbon tetrachloride subcutaneously. Then the expression of laminin and integrin alpha 6 subunit was observed by immunohistochemistry and dot immuno-blotting. RESULTS: We observed sinusoidal capillaration formed by deposition of laminin along sinusoids in Disse interspace by immunohistochemistry staining. In normal rat the expression of integrin alpha 6 was restricted to portal vascular endothelial cells and bile duct epithelial cell membranes. No expression was observed in sinusoidal endothelial cell membranes. When capillaration integrin alpha 6 was detected in a continuous pattern along the sinusoids, the content of integrin alpha 6 was significantly higher in fibrotic liver tissues than in normal liver tissues as measured by dot immuno-blotting (P<0.05). CONCLUSIONS: During fibrogenesis, laminin continuously accumulate in liver tissues and form basement membrane resulting in sinusoidal capillaration, and then induce the expression of integrin alpha 6 on SEC membranes.

Animals↗
PubMed2003

[Laminin and its alpha 6 integrin receptor in the regulation of human hepatocellular carcinoma cell phenotypes].

OBJECTIVE: To study the role of integrin alpha 6 in cell attachment, spread, survival/proliferation and differentiation of human hepatocellular carcinoma (HCC) BEL-7402 cells on various substrates by monoclonal antibody against the extracellular domain of alpha 6 subunit (IA6ED McAb). METHODS: The effect of McAb on attachment and spread of BEL-7402 cells on LN or FN substrate was examined. MTT analysis was used to examine the cell survival/proliferation, gelatin zymography to the matrix metalloproteinases (MMPs) secreted by BEL-7402 cells, and microparticle immunoabsorbent kit to AFP secretion while the cells were cultured on LN-, FN- or Matrigel-coated substrates. RESULTS: The cell attachment, spread and survival/proliferation were inhibited. Moreover importantly, the malignant cell dedifferentiation and abnormal differentiation on LN-coated substrate were also strongly inhibited by IA6ED McAb. CONCLUSION: LN and integrin alpha 6 regulate human HCC cell phenotypes of survival/proliferation and differentiation. The phenotypes of dedifferentiation and abnormal differentiation can be reversed by blocking the interaction between integrin alpha 6 and LN using IA6ED McAb, which may lower metastatic potency of tumor cells.

Antibodies, Monoclonal↗
PubMed2006

Optimal combination chemotherapy and chemoradiotherapy with etoposide for advanced cervical squamous cancer cells in vitro.

Patients with unresectable advanced carcinoma of the uterine cervix are usually treated with chemotherapy or chemoradiotherapy. In the present study, the optimal administration protocol for etoposide in chemotherapy and chemoradiotherapy for advanced cervical cancer patients was investigated in vitro using the radio-sensitive and anticancer drug-sensitive human cervical squamous cell carcinoma cell line ME180. Therapeutic doses of concurrent irradiation reduced the cellular etoposide sensitivity in a dose-dependent manner, while postirradiation-surviving subclones established from repeatedly irradiated ME180 cells showed significantly higher etoposide sensitivities than the non-irradiated parent cells. Of the 6 monoclonal etoposide-resistant subclones established from ME180 cells, 5 were significantly radioresistant. Although the etoposide-resistant subclones were also significantly resistant to other anticancer drugs, such as cisplatin, carboplatin, nedaplatin, pirarubicin, paclitaxel and docetaxel, they were more sensitive to 5-fluorouracil, mitomycin C and SN38 than the parent cells. Flow cytometric analyses revealed that the etoposide-resistant subclones showed significantly increased cell surface expression of CD40 compared to the parent cells, which expressed undetectable levels of CD40. However, the expression of some integrin receptor subunits, such as CD29, CD49a and CD49f, was apparently reduced in the etoposide-resistant subclones. These results indicate that etoposide should be administered to advanced cervical squamous cancer patients after the completion of radiotherapy, rather than as a concurrent chemoradiotherapy. In order to kill surviving etoposide-resistant cancer cells more effectively, 5-fluorouracil, mitomycin C and irinotecan may be candidate combination drugs for use with etoposide. Differential expression of integrin receptors and CD40 may be involved in the acquisition of etoposide resistance by cervical squamous cancer cells.

Antigens, CD20↗