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PubMed2001

Teratogenic effects of Doxorubicin in rats at midgestation and at term.

Doxorubicin (DOXO) is an anticancer drug widely used against leukaemias and solid tumours. Doxorubicin is teratogenic in laboratory species, as demonstrated by a number of in vivo and in vitro experiments. In our in vitro study, the endoderm of the primitive gut and the caudal mesenchymes have been the main target tissues, while oxidative stress has been excluded as a mechanism in Doxorubicin-related abnormalities. The aims of the present work are the confirmation of our previous in vitro results (obtained on rat embryos cultured from 9.5 to 11.5 d.p.c.) in an in vivo model (midgestation) and the comparison of the abnormalities observed in the embryos at midgestation with malformations observable at term of pregnancy. For this purpose, pregnant rats were i.p. treated on 9.5 and 10.5 d.p.c. with DOXO. Embryos were analysed on 11 d.p.c., while foetuses were externally and viscerally analysed on 20 d.p.c. (term of gestation). The data collected at midgestation confirm the specific embryotoxic effects (particularly to the primitive gut and the caudal mesenchyme) previously observed in vitro. The data collected at term show the endoderm derivatives (gastrointestinal apparatus and respiratory tract) as the primary target organs, supporting the idea that the teratogenic activity of Doxorubicin is mediated by specific toxic effects directed to the primitive gut.

Abnormalities, Drug-Induced↗
PubMed1978

Teratogenicity of adriamycin and daunomycin in the rat and rabbit.

The antitumor drugs adriamycin and daunomycin were evaluated for effects on embryonal and fetal development in the rat and rabbit. Doses of adriamycin ranging from 1-2 mg/kg/day or daunomycin ranging from 1-4 mg/kg/day were administered ip to pregnant rats on days 6-15, 6-9, 9-12 or 12-15 of gestation. Both drugs were teratogenic in the rat, particularly when administered on days 6-15 or 6-9 of gestation. Relatively few anomalies resulted from treatment on days 9-12 or 12-15. On a mg/kg basis, adriamycin was the more potent teratogen, producing major anomalies at doses as low as 1.25 mg/kg. Similar anomalies, but at a lower incidence, were produced by daunomycin at dose levels of 4 mg/kg. Characteristic malformations included esophageal and intestinal atresia, tracheo-esophgeal fistula, hypoplasia of the urinary bladder and various cardiovascular anomalies. Neither drug was teratogenic when given iv to rabbits at doses up to and including 0.6 mg/kg/day on days 6-18 of gestation, but a high incidence of abortion occurred in rabbits treated with adriamycin.

Abnormalities, Drug-Induced↗
PubMed1988

Teratogen update: anesthetic agents.

Although many pregnant women undergo anesthesia and many others are occupationally exposed to anesthetics every year, assessment of the teratogenic risk of anesthetic agents in humans must currently be made on the basis of very limited data. Available studies suggest that administration of an anesthetic to a pregnant woman will usually not have a deleterious effect on embryonic or fetal development. The risk of congenital anomalies does not appear to be substantially increased among children of women who have chronic occupational exposure to anesthetic gases during pregnancy, either, but miscarriages may occur more frequently than expected among such women. There is an urgent need for publication of good human epidemiologic and experimental animal studies on the teratogenicity of anesthetics.

Anesthesia, General↗
PubMed1988

Postimplantation development of mitomycin C-treated mouse blastocysts.

Treatment of morula-stage mouse embryos with mitomycin C (0.004-0.5 microgram/ml) in vitro resulted in a decrease in the number of inner cell mass (ICM) cells at the blastocyst stage. The trophectoderm population was reduced only at the highest dosage (0.5 microgram/ml) tested. Postblastocyst development in vitro was retarded: Fewer embryos formed trophoblastic outgrowth, and the ICM was poorly developed. The embryo transfer experiments demonstrated that a reduction in ICM cell numbers diminished the potential of embryogenesis. The presence of a sufficient number of trophoblasts and ICM cells in the blastocyst is therefore a prerequisite for successful implantation and embryogenesis. The mitomycin-treated blastocysts with only 70% of normal ICM cells developed to egg cylinders that were about half normal size, but by days 12-14 the body size of the surviving embryo was similar to that of the control embryo. Morphogenesis was retarded during the early organogenesis stages, but only a slight delay was seen in the treated embryo on day 12. Such observation strongly suggests that a restorative phase of growth and morphogenesis has occurred during the immediate postimplantation period.

Animals↗
PubMed1992

In vitro exposure of preimplantation mouse embryos to cocaine and benzoylecgonine inhibits subsequent development.

Cocaine is used by over 20% of women of reproductive age. Although there have been numerous studies focusing on its effects on reproductive processes, none has evaluated its direct effect on preimplantation development. We have investigated the effect of cocaine and its major metabolite, benzoylecgonine, on in vitro preimplantation mouse embryogenesis. One-cell embryos were exposed at the one-, two-, four-, or eight-cell stage for 24 hr to medium containing 0-400 micrograms/ml cocaine or benzoylecgonine and then cultured to the blastocyst stage. Cocaine had its strongest inhibitory effect at the earliest stages of development. At the one- and two-cell stages, there was a significant inhibition of blastocyst formation following exposure to cocaine concentrations of 25-400 micrograms/ml, and at the four-cell stage there was an inhibitory effect at 100 and 400 micrograms/ml cocaine. Benzoylecgonine inhibited the development of embryos to blastocyst only at the one- and two-cell stages, at concentrations of 100-400 micrograms/ml. These findings suggest that cocaine is capable of blocking preimplantation embryogenesis, particularly following exposure at the earliest stages, and that this toxicity may abate as cocaine is biotransformed to benzoylecgonine.

Animals↗
PubMed1992

A comparison of sodium arsenite- and hyperthermia-induced stress responses and abnormal development in cultured postimplantation rat embryos.

Acute exposures to sodium arsenite (50 microM) were embryotoxic in day 10 rat embryos exposed in vitro. Sodium arsenite-induced embryotoxicity was characterized by decreased growth (crown-rump length, somite number, and embryo protein content) and abnormal development (hypoplastic prosencephalon, abnormal somites, and abnormal flexion of the tail). At embryotoxic exposures, sodium arsenite also induced the synthesis of three heat shock proteins (hsps), one of which is recognized by a monoclonal antibody specific for the heat-inducible hsp 72. In addition, sodium arsenite induced the accumulation of heat-inducible hsp 70 mRNA. Although the abnormal morphologies induced by sodium arsenite and hyperthermia appear to be different, the stress response as measured by the synthesis of hsps, the accumulation of hsp 72 protein, and the accumulation of hsp 70 mRNA is similar in embryos exposed to these two embryotoxic agents. Thus, sodium arsenite and hyperthermia both induce a stress response; however, the relationship between the induction of a stress response and the subsequent abnormal development that ensues is unclear.

Animals↗
PubMed1994

Prevention of neural tube defects by and toxicity of L-homocysteine in cultured postimplantation rat embryos.

Mild hyperhomocysteinemia is frequently observed in mothers who gave birth to a child with a neural tube defect (NTD). In a previous study we showed L-homocysteine was embryotoxic to gestational day 10 (GD10) rat embryos in culture, however, no NTDs were observed. We therefore investigated the effect of L-homocysteine on the development of neural plate stage (GD9.5) rat embryos. Other objectives of this study were investigation into whether the embryotoxicity of L-homocysteine could be attenuated by compounds related to its metabolism and clarification of the mechanism of L-homocysteine embryotoxicity. In GD9.5 rat embryos L-homocysteine was not toxic at 1- and 2-mM concentrations. Rather at these concentrations it promoted development of the rat embryos in serum that without supplementation caused NTDs in the embryos. L-Methionine had the same preventive effect at even lower concentrations, but folinic acid (1 mM) did not improve embryonic development. N5-Methyltetrahydrofolate (5-CH3-THF) (100 microM), L-serine (6 mM), and L-methionine (6 and 12 mM) attenuated the embryotoxicity of L-homocysteine (6 mM) in GD10 rat embryos. Vitamin B12 (10 microM) completely abolished the embryotoxicity of L-homocysteine, which was shown to be mediated by catalysis of the spontaneous oxidation of L-homocysteine to the less toxic L-homocystine. In GD11 rat embryos, both L- and D-homocysteine were readily taken up when added to the culture (3 mM) and increased embryonic S-adenosylhomocysteine (SAH) levels 14- and 3-fold, respectively. This difference was shown to be caused by the stereospecific preference of SAH hydrolase. We propose the basis for L-homocysteine embryotoxicity is an inhibition of transmethylation reactions by increased embryonic SAH levels.

Adenosylhomocysteinase↗
PubMed2000

Suppression subtractive hybridization identifies genes expressed in oviduct during mouse preimplantation period.

Fertilization and development of mouse embryos occur in the ampullae of oviduct. Various growth factors and embryotrophic factors produced by the oviductal cells have been demonstrated to enhance embryo development in vitro. As a step towards understanding the genetic changes of mouse oviduct during mouse embryos preimplantation period, we adopted suppression subtractive hybridization (SSH) to establish four subtracted cDNA libraries to identify (1) oviduct-expressing genes, and (2) genes that may support embryo development in vivo. Using this method, we isolated 82, 88, 99, and 109 clones from four mouse libraries prepared from 0 (day 0), 24 (day 1), 48 (day 2), and 72 h (day 3) post-human chorionic gonadotropin (hCG) treated mice. Reverse dot-blot analysis confirmed that 25 (day 0), 24 (day 1), 40 (day 2), and 29 (day 3) clones were highly expressed in mouse oviduct when compared to other tissues. DNA sequence analysis identified genes encoding mouse oviduct-specific glycoprotein (MOGP), actin-binding protein 280, and several viral genes. Northern analysis confirmed that the genes were mainly expressed in oviduct, with some viral genes also expressed in uterus. About 9% of these oviduct expressing clones (11/118) were novel. We further demonstrated that one of the novel clones ODEG0-17 was expressed in the oviduct during early embryo preimplantation period and rarely in other tissues by RT-PCR. Our results show that SSH is a powerful method applicable to identifying tissue-specific transcripts on fertilization and development.

Animals↗
PubMed1993

Regulation of myogenesis in paralyzed muscles in the mouse mutants peroneal muscular atrophy and muscular dysgenesis.

The roles of innervation, muscle electrical activity, and muscle contraction in regulating the formation and survival of primary and secondary myotubes during embryonic and fetal development of skeletal muscle were studied using the mouse mutants peroneal muscular atrophy (pma) and muscular dysgenesis (mdg). The pma phenotype includes the absence of the peroneal division of the sciatic nerve, so muscles in the anterior compartment of the lower hindlimb are aneural throughout development. Muscles in mdg mice are paralyzed due to the absence of excitation-contraction coupling and hyperinnervated due to suppression of motoneuron death in consequence of their paralysis, but otherwise are electrically excitable and receive synaptic transmission. In a quantitative comparison between control and mutant extensor digitorum longus (EDL) muscles at E15, primary myotube numbers were depressed by 20-30% in both mutants and in paralyzed or denervated muscles from control strain animals. The number of secondary myotubes, however, was normal in pma mutants and two and a half times greater than normal in the hyperinnervated mdg EDL muscles, so that the ratio of secondary to primary myotubes was increased by 300% in the mutant with respect to heterozygous or -/- littermates. Chronic paralysis with tetrodotoxin (TTX) caused no further depression of primary myotube numbers in aneural pma muscles, but secondary myotube numbers were reduced by 40%, reducing the ratio of secondary to primary myotubes by 35%. We conclude that during normal development the generation of secondary myotubes depends on neurally evoked electrical activity in primary myotubes, which stimulates mitosis of secondary myoblasts. The effect of TTX shows that aneural pma primary myotubes discharge spontaneous myogenic action potentials, while mdg muscles may receive greater than normal electrical activation due to their hyperinnervation, explaining the presence and numbers of secondary myotubes in the mutant mouse muscles.

Action Potentials↗
PubMed1994

Regulation of Na+,K(+)-ATPase alpha subunit gene expression during mouse preimplantation development.

Several lines of evidence support the hypothesis that a sodium flux, driven by Na+,K(+)-ATPase in the basolateral plasma membranes of mural trophectoderm, drives fluid transport during blastocoel formation in eutherians. In light of the importance of this enzyme for preimplantation development, attention has been focused on the regulation of expression of its alpha and beta subunits. Here we report on the spatial distribution and translation of the alpha subunit mRNA. Although this mRNA accumulates from the 2-cell stage onward the alpha subunit itself could not be detected by immunofluorescence prior to the late morula stage, after which it becomes concentrated in the mural trophectoderm. In the present study we have used a wholemount, fluorescent in situ hybridization technique that takes advantage of the optical sectioning capability of the confocal microscope to show that alpha subunit mRNA, in contrast to the alpha subunit itself, accumulates in all cells of the early blastocyst. This finding demonstrates that the spatial distribution of the alpha subunit is regulated post-transcriptionally. We have also examined the translational regulation of alpha subunit mRNA by preparing polyribosomal and subribosomal ribonucleoprotein fractions for mRNA assay by reverse transcription-polymerase chain reaction. We found that alpha subunit mRNA is in polyribosomes continuously from at least the 4-cell stage. Thus, the abrupt appearance of the alpha subunit in the late morula stage as revealed by immunofluorescence must be determined by post-translational events. In the Discussion, we consider the hypothesis that synthesis of the beta subunit of the enzyme is the rate limiting step in functional expression of the alpha subunit.

Animals↗
PubMed1995

Stage-specific induction and regulation by genomic imprinting of the mouse U2afbp-rs gene during preimplantation development.

The mouse U2afbp-rs gene is imprinted and expressed exclusively from the paternal allele in the adult. To determine whether the U2afbp-rs gene is regulated by imprinting in the early embryo and to examine its normal temporal pattern of expression, we used a new quantitative RT-PCR approach to compare U2afbp-rs gene expression between androgenetic and gynogenetic embryos and to monitor U2afbp-rs expression during normal preimplantation embryogenesis. The U2afbp-rs gene is transcriptionally induced transiently at the 2-cell stage, making it one of the first genes ever identified with this pattern of regulation. At the 2-cell stage, androgenones express approximately twice as much U2afbp-rs mRNA as normal embryos, while gynogenones express much less. Thus, genomic imprinting regulates the U2afbp-rs gene from the time of its initial induction, distinguishing it from some other autosomal imprinted genes that have been analyzed (e.g., Igf2r and Igf2). Because the function of the U2afbp-rs protein has not been determined, the significance of transient induction of the U2afbp-rs gene at the 2-cell stage is not clear. Our data indicate that abundant expression of the U2afbp-rs gene is not essential for early development since gynogenones form blastocysts at a high frequency.

Animals↗
PubMed1996

Defective chorioallantoic fusion in mid-gestation lethality of parthenogenone<-->tetraploid chimeras.

Previous studies of parthenogenetic embryos revealed severe perturbations of both embryonic and extraembryonic tissue lineages during postimplantation development. The majority of pure parthenogenetic concepti have no recognizable axis and exhibit preferential terminal differentiation of their trophectoderm and primitive endoderm. To further define the role of the extraembryonic lineages in parthenogenetic development, we provided them with zygote-derived extraembryonic tissues by aggregating them with fertilized tetraploid embryos. On Day 12 of combined in vitro and in vivo development, most of the embryos proper in these chimeras were entirely derived parthenogenetically, whereas their trophectoderm and primitive endoderm tissues were derived from the tetraploid component. No Igf2 expression was detected in the parthenogenetic embryo proper, indicating that imprinting was manifested in such chimeras. Typical development of the parthenogenetic embryo proper was markedly improved in comparison with pure parthenogenetic concepti, with such chimeras attaining an average of 23 somites (range, 10 to 35). However, most of the chimeras died abruptly at Day 13, and all were being resorbed at Day 14 of development. The gross normality of axial structures and organ development suggests that a major cause of failure of these chimeric parthenogenones to survive beyond mid-gestation was due to defective chorioallantoic fusion. Our results indicate that the severe perturbation of axial development seen in most pure parthenogenetic concepti is a secondary consequence of the effects of parthenogenesis on the trophectoderm and primitive endoderm lineages. Moreover, the mid-gestation death of parthenogenetic embryos proper despite the presence of zygote-derived tetraploid tissues implicates extraembryonic mesoderm in manifesting the effects of genomic imprinting.

Allantois↗
PubMed1998

Na/K-ATPase-mediated 86Rb+ uptake and asymmetrical trophectoderm localization of alpha1 and alpha3 Na/K-ATPase isoforms during bovine preattachment development.

This study evaluated Na/K-ATPase alpha 1- and alpha 3-subunit isoform polypeptide expression and localization during bovine preattachment development. Na/K-ATPase cation transport activity from the one-cell to blastocyst stage was also determined by measuring ouabain-sensitive 86Rb+ uptake. Both alpha1- and alpha 3-subunit polypeptides were detected by immunofluorescence to encircle the entire cell margins of each blastomere of inseminated zygotes, cleavage stage embryos, and morulae. Immunofluorescent localization of alpha1-subunit polypeptide in bovine blastocysts revealed an alpha1 immunofluorescence signal confined to the basolateral membrane margins of the trophectoderm and encircling the cell periphery of each inner cell mass (ICM) cell. In contrast, alpha 3-subunit polypeptide immunofluorescence was localized primarily to the apical cell surfaces of the trophectoderm with a reduced signal present in basolateral trophectoderm regions. There was no apparent alpha 3-subunit signal in the ICM. Analysis of 86Rb+ transport in vitro demonstrated ouabain-sensitive activity throughout development from the one-cell to the six- to eight-cell stage of bovine development. 86Rb+ uptake by morulae (day 6 postinsemination) did not vary significantly from uptake detected in cleavage stage embryos; however, a significant increase was measured at the blastocyst stage (P < 0.05). Treatment of embryos with cytochalasin D (5 micrograms/ml) did not influence 86Rb+ uptake in cleavage stage embryos. Cytochalasin D treatment however was associated with a significant rise in ion transport in morulae and blastocysts (13.49 and 61.57 fmol/embryo/min, respectively) compared to untreated controls (2.65 and 22.83 fmol/embryo/min, respectively). Our results, for the first time, demonstrate that multiple Na/K-ATPase alpha-subunit isoforms are distributed throughout the first week of mammalian development and raise the possibility that multiple isozymes of the Na/K-ATPase contribute to blastocyst formation.

Animals↗
PubMed1998

Expression of inositol 1,4,5-trisphosphate receptors in mouse oocytes and early embryos: the type I isoform is upregulated in oocytes and downregulated after fertilization.

A fertilization-induced increase in intracellular Ca2+ is responsible for initiating all of the events of egg activation. In mammals, the Ca2+ increase takes the form of a series of Ca2+ oscillations showing complex temporal and spatial properties. To understand the nature of these changes, we have investigated the expression patterns of the three isoforms of the inositol trisphosphate receptor (InsP3R) during oocyte maturation and preimplantation development. We find that mouse oocytes express mRNAs for all three InsP3R subtypes. Semiquantitative ratio reverse-transcriptase polymerase chain reaction shows that the type II isoform is the predominant message in mature oocytes, representing 67% of the InsP3R mRNA. In contrast, protein analysis reveals that the type I isoform accounts for all of the detectable InsP3R protein, despite representing only 20% of the InsP3R mRNA. The levels of InsP3R protein were examined to determine whether they correlated with the Ca2+ signaling events surrounding the fertilization process. Type I InsP3R protein increased during oocyte maturation and, in addition, within 8 h of fertilization underwent a dramatic decrease. During development to the blastocyst the level of type I InsP3R protein did not return to prefertilization levels and types II and III remained below our detection limit. The decrease in InsP3R protein after fertilization was found to correlate with a decrease in the sensitivity of InsP3-induced Ca2+ release. These studies show that the expression of InsP3R mRNA is developmentally regulated, that Ca2+ signaling at fertilization is mediated exclusively through the type I InsP3R, and that the InsP3R is downregulated after fertilization.

Animals↗
PubMed1999

Dynamic expression of lunatic fringe suggests a link between notch signaling and an autonomous cellular oscillator driving somite segmentation.

The metameric organization of the vertebrate trunk is a characteristic feature of all members of this phylum. The origin of this metamerism can be traced to the division of paraxial mesoderm into individual units, termed somites, during embryonic development. Despite the identification of somites as the first overt sign of segmentation in vertebrates well over 100 years ago, the mechanism(s) underlying somite formation remain poorly understood. Recently, however, several genes have been identified which play prominent roles in orchestrating segmentation, including the novel secreted factor lunatic fringe. To gain further insight into the mechanism by which lunatic fringe controls somite development, we have conducted a thorough analysis of lunatic fringe expression in the unsegmented paraxial mesoderm of chick embryos. Here we report that lunatic fringe is expressed predominantly in somite -II, where somite I corresponds to the most recently formed somite and somite -I corresponds to the group of cells which will form the next somite. In addition, we show that lunatic fringe is expressed in a highly dynamic manner in the chick segmental plate prior to somite formation and that lunatic fringe expression cycles autonomously with a periodicity of somite formation. Moreover, the murine ortholog of lunatic fringe undergoes a similar cycling expression pattern in the presomitic mesoderm of somite stage mouse embryos. The demonstration of a dynamic periodic expression pattern suggests that lunatic fringe may function to integrate notch signaling to a cellular oscillator controlling somite segmentation.

Animals↗
PubMed2000

Developmental change in TATA-box utilization during preimplantation mouse development.

Activation of the embryonic genome during preimplantation mouse development is characterized by a marked reprogramming of gene expression that is essential for further development. Expression of the protein translation initiation factor eIF-1A gene is driven by a proximal TATA-containing promoter and a distal TATA-less promoter. Using specific amplification of cDNA ends that resolves transcripts derived from the TATA-less and TATA-containing promoters, we find that 70% of the eIF-1A transcripts are derived from the TATA-containing promoter in the fully-grown oocyte. Activation of the embryonic genome during the two-cell stage is accompanied by a change in promoter utilization such that only 25% of the transcripts are now derived from the TATA-containing promoter, i.e., 75% are derived from the TATA-less promoter. When one-cell embryos are cultured to the two-cell stage in the presence of alpha-amanitin, this change in transcript abundance is not observed, i.e., the distribution of transcripts is similar to that observed in the oocyte. By the blastocyst stage only 5% of the transcripts are generated from the TATA-containing promoter. If the change in TATA-box utilization for the eIF-1A reflects an underlying global change in TATA-box utilization, a dramatic change in promoter utilization may occur during preimplantation development such that TATA-less promoters are more efficiently utilized. Such a change in promoter utilization could contribute significantly to the reprogramming of gene expression that occurs during the maternal-to-zygotic transition.

Animals↗
PubMed1997

An oocyte-specific methylation imprint center in the mouse U2afbp-rs/U2af1-rs1 gene marks the establishment of allele-specific methylation during preimplantation development.

An oocyte-specific methylation imprint mark region, consisting of approximately 200 bp from the mouse imprinted gene U2afbp-rs, was identified within an area containing a CpG island and a short tandem repeat sequence. The oocyte-specific methylation was preserved in fertilized eggs and then expanded on the repressed maternal allele during preimplantation development until the adult methylation pattern was achieved by 12.5 days of embryonic development. These results indicate that the oocyte-specific imprinting mark region acts as a center in establishing the hypermethylated region on the repressed maternal allele. Furthermore, a region that is hypermethylated in both gametes was identified but its hypermethylation was conserved only on the maternal allele during preimplantation development, suggesting that some factor(s) inherited from oocytes may act to maintain hypermethylation on the maternal allele.

Alleles↗
PubMed1999

Expression of tenascin in human cervical cancer--association of tenascin expression with clinicopathological parameters.

OBJECTIVE: Tenascin is an extracellular matrix glycoprotein, relevant for embryonal and fetal development, which is reexpressed in the stroma of benign and malignant tumors. Little is known about the molecular interaction of tenascin during neoplastic transformation and tumor progression in cervical cancer. METHOD: We studied the expression of tenascin in normal tissue of the cervix uteri, cervical carcinoma in situ, and invasive cervical carcinoma in paraffin sections by immunohistochemistry using a monoclonal antibody. Tenascin immunoreactivity was compared with various prognostic parameters. RESULTS: In normal cervical tissue (n = 5) and in cervical carcinoma in situ (n = 10) only vessel walls showed a weak tenascin cross-reactivity, whereas tenascin was not expressed in the epithelial layer or the underlying connective tissue. In invasive cervical carcinoma (n = 89) tenascin expression was markedly increased. In 84% (n = 75) of the cases examined a strong tenascin immunoreactivity was noted around and within the tumor cell nests. Sixteen percent (n = 14) of infiltrating cervical carcinomas showed no tenascin immunoreactivity. A definite correlation was found between weak or no tenascin expression and slight desmoplastic mesenchymal reactivity (n = 42/91%, P < 0.001), lymphatic space invasion (n = 54/81%, P < 0.001), and lymph node metastases (n = 30/77%, P < 0.05). Tenascin-positive patients had a significantly better prognosis than tenascin-negative patients (mean survival time of 56.5 +/- 4.1 months versus 31.9 +/- 5.6 months, P < 0.05). CONCLUSION: Based on these findings we discuss that the appearance of tenascin is an indicator of an adequate biological defense in cervical cancer patients. The tenascin staining may therefore be useful for detecting a subgroup of invasive cancer patients missing tenascin reactivity with alterations of stromal defense and a poorer prognosis.

Carcinoma in Situ↗