Stromal matrix metalloproteinase-11 is involved in the mammary gland postnatal development.

MMP-11 is a bad prognosis paracrine factor in invasive breast cancers. However, its mammary physiological function remains largely unknown. In the present study we have investigated MMP-11 function during postnatal mammary gland development and function using MMP-11-deficient (MMP-11-/-) mice. Histological and immunohistochemical analyses as well as whole-mount mammary gland staining show alteration of the mammary gland in the absence of MMP-11, where ductal tree, alveolar structures and milk production are reduced. Moreover, a series of transplantation experiments allowed us to demonstrate that MMP-11 exerts an essential local paracrine function that favors mammary gland branching and epithelial cell outgrowth and invasion through adjacent connective tissues. Indeed, MMP-11-/- cleared fat pads are not permissive for wild-type epithelium development, whereas MMP-11-/- epithelium transplants grow normally when implanted in wild-type cleared fat pads. In addition, using primary mammary epithelial organoids, we show in vitro that this MMP-11 pro-branching effect is not direct, suggesting that MMP-11 acts via production/release of stroma-associated soluble factor(s). Finally, the lack of MMP-11 leads to decreased periductal collagen content, suggesting that MMP-11 has a role in collagen homeostasis. Thus, local stromal MMP-11 might also regulate mammary epithelial cell behavior mechanically by promoting extracellular matrix stiffness. Collectively, the present data indicate that MMP-11 is a paracrine factor involved during postnatal mammary gland morphogenesis, and support the concept that the stroma strongly impact epithelial cell behavior. Interestingly, stromal MMP-11 has previously been reported to favor malignant epithelial cell survival and promote cancer aggressiveness. Thus, MMP-11 has a paracrine function during mammary gland development that might be harnessed to promote tumor progression, exposing a new link between development and malignancy.

Deficiency in trefoil factor 1 (TFF1) increases tumorigenicity of human breast cancer cells and mammary tumor development in TFF1-knockout mice.

Although trefoil factor 1 (TFF1; previously named pS2) is abnormally expressed in about 50% of human breast tumors, its physiopathological role in this disease has been poorly studied. Moreover, controversial data have been reported. TFF1 function in the mammary gland therefore needs to be clarified. In this study, using retroviral vectors, we performed TFF1 gain- or loss-of-function experiments in four human mammary epithelial cell lines: normal immortalized TFF1-negative MCF10A, malignant TFF1-negative MDA-MB-231 and malignant TFF1-positive MCF7 and ZR75.1. The expression of TFF1 stimulated the migration and invasion in the four cell lines. Forced TFF1 expression in MCF10A, MDA-MB-231 and MCF7 cells did not modify anchorage-dependent or -independent cell proliferation. By contrast, TFF1 knockdown in MCF7 enhanced soft-agar colony formation. This increased oncogenic potential of MCF7 cells in the absence of TFF1 was confirmed in vivo in nude mice. Moreover, chemically induced tumorigenesis in TFF1-deficient (TFF1-KO) mice led to higher tumor incidence in the mammary gland and larger tumor size compared with wild-type mice. Similarly, tumor development was increased in the TFF1-KO ovary and lung. Collectively, our results clearly show that TFF1 does not exhibit oncogenic properties, but rather reduces tumor development. This beneficial function of TFF1 is in agreement with many clinical studies reporting a better outcome for patients with TFF1-positive breast primary tumors.

Amplification and invasiveness of epithelial progenitors during gastric carcinogenesis in trefoil factor 1 knockout mice.

OBJECTIVE: It is not known whether or not epithelial progenitors of the pyloric antrum are involved in gastric carcinogenesis. Normally, these progenitors give rise to two main cell lineages: pit and gland mucous cells. This study was designed to examine the changes that occur in pyloric antral mucous cell lineages and their progenitors during development of gastric adenoma and carcinoma in trefoil factor 1 (TFF1) knockout mice. MATERIALS AND METHODS: Pyloric antral mucosal tissues of TFF1 knockout mice at ages from 3 days to 17 months were processed for histochemical analysis using Ulex europaeus and Grifforia simplifolica lectins as markers for pit and gland mucous cells, respectively. The dividing epithelial progenitors were identified by using immunohistochemical and electron microscopy techniques. RESULTS: TFF1 loss was associated with amplification of both mucus-secreting pit and gland cells. Both lectins examined bound not only to mature mucous cells, but also to most of epithelial progenitors which gradually amplified with age and frequently were seen in mitosis. Analysis of 12- to 17-month-old TFF1-deficient stomachs revealed occasional groups of poorly differentiated mucosal cells with features similar to those of epithelial progenitors (or stem cells), in the basal portion of the antral mucosa. These cells eventually invaded the muscularis mucosa while maintaining some capacity to differentiate. CONCLUSION: This study shows that the progenitors of pit and gland mucous cells contribute to gastric carcinogenesis in the pyloric antrum of TFF1 knockout mice, strongly supporting the concept of stem cell origin of cancer.

Matrix metalloproteinase-11/stromelysin-3 exhibits collagenolytic function against collagen VI under normal and malignant conditions.

The substrate of matrix metalloproteinase 11 (MMP11) remains unknown. We have recently shown that MMP11 is a negative regulator of adipogenesis, able to reduce and even to revert mature adipocyte differentiation. Here, we have used mouse 3T3L1 cells and human U87MG and SaOS cells to show that MMP11 cleaves the native alpha3 chain of collagen VI, which is an adipocyte-related extracellular matrix component. It is known that extracellular proteolytic processing of this chain is required for correct collagen VI folding. Interestingly, MMP11-deficient fat tissue is less cohesive and exhibits collagen VI alteration, dramatic adipocyte plasma and basement membrane abnormalities and lipid leakage. MMP11 is thus required for correct collagen VI folding and therefore for fat tissue cohesion and adipocyte function. Both MMP11 and collagen VI favor tumor progression. Similar spatio-temporal overexpression at the adipocyte-cancer cell interface has been reported for the two proteins. MMP11-dependent collagen VI processing might therefore be expected to occur during malignancy. Accordingly, collagen VI no longer delineates adipocytes located at the invasive front of breast carcinomas. In conclusion, the native alpha3 chain of collagen VI constitutes a specific MMP11 substrate. This MMP11 collagenolytic activity is functional in fat tissue ontogenesis as well as during cancer invasive steps.

Cannabis and driving: results from a general population survey.

The role of illicit drugs on driving, and particularly of cannabis and driving, is the object of increasing awareness. While there is increasing evidence of their effect on psychomotor performance and increased risk of involvement in traffic accidents, limited information is available concerning factors that can predict the likelihood of driving under the influence of cannabis. The present study aims to determine the past year prevalence of driving under the influence of cannabis, and of being a passenger in a vehicle driven by a person under the influence of cannabis, as well as to examine the correlations with a broad range of potential risk factors. A total of 2500 people, aged between 14 and 70 and living in Castille and Leon (Spain), were surveyed in 2004 with regard to their consumption of alcohol and illicit drugs. Among those who reported cannabis use in the previous year, further assessment was carried out. 15.7% of those surveyed reported cannabis consumption in the previous 12 months, of whom 9.7% reported driving a vehicle under the influence of cannabis during this period, on average eight times. One out of five (19.9%) reported being a passenger in a vehicle driven by a person under the influence of cannabis, on average five times in the previous 12 months. The predictors of driving under the influence of cannabis were the population size of community, the number of drugs consumed, reference to cannabis-related problems and to being a passenger in a vehicle driven by a person under the influence of alcohol. The data show that cannabis consumption and driving is common, and requires more attention from policy makers.

[Paradoxical interactions between pregnancy and breast cancer]. / Effets paradoxaux de la grossesse sur le cancer du sein.

Interactions between pregnancy and breast cancer are complex and paradoxical. Epidemiological data show that nulliparity and late full-term pregnancy increase breast cancer risk. By contrast, early full-term pregnancy and multiparity are thought to be the most effective means of decreasing lifetime breast cancer risk. Paradoxically, young women diagnosed with breast cancer during pregnancy have a higher risk of dying from their disease. Moreover, there is a transient increase in risk of breast cancer in the first three to four years after pregnancy. After breast cancer treatment, there is no evidence that pregnancy increases the risk of breast cancer recurrence. Thus, it is not contraindicated in women previously treated for breast cancer and free of recurrence. Various physio-pathological mechanisms are involved in the protective effect of pregnancy, like cellular differentiation of mammary cells, mammary gland involution, circulating anti-mucin antibody and excretion in the milk of breast carcinogens. In the past, unfavorable effects of pregnancy were mainly attributed to precancerous cell proliferation induced by pregnancy-associated hormonal changes. However, recent studies suggest that the remodeling of cellular microenvironment and extracellular matrix during pregnancy and involution may contribute to enhanced invasive and metastatic potential of breast carcinomas.

Expression of TFF3 during multistep colon carcinogenesis.

The pathogenesis of colon cancer is not well understood. This common type of cancer is generally believed to occur in a multistep process which involves alterations of various tumor suppressor genes and oncogenes during the progression through benign lesions towards carcinoma. TFF3 is a product of the colonic epithelium and has been implicated in colonic mucosal protection and also in the aggressiveness of colon cancer cells. The aim of this study was to analyze the expression of TFF3 during propagation towards cancer development in the human colon. Colonic tissues representing colitis, adenomatous polyposis, tubulovillous adenoma, and mucoid/adeno-carcinomas were processed for immunohistochemistry using an antibody specific for human TFF3. The results were correlated with those of PCNA-labeling, quantified, and compared with those of control tissues obtained from the safe margin of macroscopically normal colonic mucosa of patients with colon cancer. The data showed marked down-regulation of TFF3 expression in adenomatous polyposis, then TFF3 expression returns to about control level during adenoma and remains high during mucoid- and adeno-carcinomas. Colonic tissues with highly invasive cancer cells were characterized by statistically significant down-regulation of TFF3 expression. The changes observed in expression of TFF3 showed an inverse correlation with cell proliferation and suggest that it might play a protective role against colon carcinogenesis.

TRAF4 overexpression is a common characteristic of human carcinomas.

Tumor necrosis factor receptor (TNFR) associated factor 4 (TRAF4) was initially identified as a gene amplified and overexpressed in breast carcinomas. Our aim was to evaluate whether TRAF4 protein overexpression exists in other cancer types. Immunohistochemistry analysis of tumor samples from 623 patients with 20 different tumor types showed that TRAF4 was overexpressed in 268 tumors (43%), including 82 of 137 lung adenocarcinomas (60%). Interestingly, 32 primary tumors and their matching metastases exhibited mostly similar TRAF4 expression pattern. TRAF4 protein overexpression was limited to cancer cells and the subcellular localization was consistently cytoplasmic in a large majority of cases. To investigate changes in TRAF4 gene copy number, 125 cases from six different types of carcinomas were also analysed by fluorescence in situ hybridization. Out of the 28 cases (22%) showing an increased TRAF4 gene copy number, 23 (82%) were overexpressing the protein. Thus, TRAF4 gene amplification is one of the mechanisms responsible for TRAF4 protein overexpression in human cancers. Considering that TRAF4 is located at 17q11.2 in a region of amplification devoid of known oncogenes and is commonly overexpressed in cancer, our data support an oncogenic role for TRAF4.

[Proteomics and breast cancer]. / Protéome et cancer du sein.

Breast cancer is the first cause of death between 35 and 55 years. Genetic alterations and modifications in gene expression are found during different steps of tumor progression. These changes are translated at the protein level where quantitative and qualitative modifications are found in tumor compared to normal samples. Similarly to studies aimed at deciphering transcriptional changes important in cancer, proteomic approaches allow the global and comparative study of proteins in normal and pathological samples. The objective of this article is to present common proteomic methods and to review the first published results concerning proteomics studies applied to breast cancer with an emphasis on reports obtained using the SELDI-TOF MS (Surface Enhanced Laser Desorption Ionization Time-Of-Flight Mass Spectrometry). In breast cancer, it is possible to explore the tumoral proteome and/or the blood derived proteome. The first studies are aimed at globally understanding the disease while the latter are aimed at discovering serum proteins or biomarkers useful for the early detection, diagnosis, prognosis and management of cancer. Promising results are obtained using these emerging methods and these novel biomarkers should be validated in the future and will have an important impact for the management of breast cancer patients.

[Circulating proteinic biomarkers and breast cancer]. / Marqueurs protéiques circulants et cancer du sein.

Circulating proteinic biomarkers are secreted by tumor cells or by their environmental cells and they have a variable specificity. In case of breast cancer, carcino-embryonic antigen (CEA) was for a long time the only circulating biomarker used. Nowadays, the most useful biomarkers measure circulating levels of fragments of MUC1-polymorphic epithelial mucin (MUC1-PEM): cancer antigen (CA) 15.3, mucin-like carcinoma-associated antigen (MCA), CA 27-29, CA 549... They are useful for general disease follow-up. Other circulating markers belonging to keratins (tissue polypeptide antigen, TPA, TPS or Cyfra 21.1) are correlated with proliferative activity of breast tumors. More recently, the measure of the c-erb B2 circulating part (extra cellular domain, ECD) was proposed as a prognostic biomarker for breast tumors with c-erb B2 overexpression. Moreover, the determination of urinary level of trefoil factor1 (PS2-TFF1) might be useful for the follow-up of hormonodependent breast cancers. The present review describes the clinical interest of these different circulating biomarkers in case of breast cancer, emphasizing their biological characteristics.

Pleiotropic effects of Trefoil Factor 1 deficiency.

Trefoil Factor 1 (TFF1), the first member of the trefoil factor family, is normally expressed in the stomach mucosa. Ectopic expression is also observed in various human pathological conditions, notably in numerous carcinomas and gastrointestinal acute inflammatory disorders. In vivo experimental data using TFF1-deficient mice highlight the pleiotropic functions of TFF1: (i) it is a gastric tumor suppressor gene involved in gastric ontogenesis and homeostasis; (ii) it protects gut mucosa from aggression; (iii) it participates in folding secreted proteins inside the endoplasmic reticulum. At the cellular level, it limits cell proliferation and apoptosis, and favors cell differentiation. Collectively, these data suggest that TFF1 may provide an alternative pharmacological tool for the prevention and treatment of human gastrointestinal diseases.

From a unique cell to metastasis is a long way to go: clues to stromelysin-3 participation.

Stromelysin-3 (ST3) overexpression is associated with poor patient clinical outcome in numerous carcinomas. The ST3 is expressed by peritumoral fibroblast-like cells. Review of the literature shows that ST3 is an active partner of cancer cells along the whole natural cancer history, and is essential for optimal tumor development as it reduces death of cancer cells invading adjacent connective tissues at the primary tumor site. Paradoxically, ST3 lowers metastasis development in vivo in mice. However, this beneficial effect does not counterbalance the deleterious anti-apoptotic function of ST3.

Trefoil factor 1 is required for the commitment programme of mouse oxyntic epithelial progenitors.

BACKGROUND: Trefoil factor 1 (TFF1/pS2) is a major secretory product of the stomach and TFF1 knockout mice constantly develop adenomas and occasional carcinomas in the pyloric antrum. AIM: To analyse the role of TFF1 in the differentiation of gastric epithelial cell lineages using oxyntic mucosae from normal and TFF1 knockout mice. METHODS: The various cell lineages were labelled using specific markers of pit, neck, parietal, and enteroendocrine cells. Patterns of TFF1, TFF2, and TFF3 expressions were defined using western blotting, immunohistochemistry, and/or immunogold electron microscopy. RESULTS: In normal mice, starting from postnatal day 1 (P1), TFF1 and TFF2 were produced by mucus secreting cells of the developing epithelium. At P7, TFF3 expression occurred in pit and parietal cells. When oxyntic glands were compartmentalised, at P21 and in older mice, TFF1 and TFF2 were expressed in pit and neck cells, respectively, and TFF3 was no longer in parietal cells but became a feature of zymogenic cells. In TFF1 deficient mice, alteration of oxyntic epithelial differentiation became obvious at P21, showing significant amplification of pit cells at the expense of parietal cells. At the molecular level, lack of TFF1 induced dramatic inhibition of TFF2 expression and more precocious TFF3 expression. CONCLUSION: In the oxyntic mucosa, all three TFFs are produced in a lineage specific manner and TFF1 is essential in maintaining the normal commitment programme of epithelial progenitors.

Cytosolic levels of neuron-specific enolase in squamous cell carcinomas of the lung.

To study the behavior and possible correlations of neuron-specific enolase (NSE) with other clinicobiological parameters, we measured the cytosolic levels of this marker by means of an immunoradiometric assay (IRMA) in 95 squamous cell lung carcinoma samples. We also analyzed the levels of pS2, tissue-type plasminogen activator (t-PA), hyaluronic acid (HA), free beta subunit of human chorionic gonadotropin (beta-HCG), CYFRA 21.1 and CA 125 in cytosol. On the cell surface we analyzed the concentrations of epidermal growth factor receptor (EGFR), HA, erbB-2 oncoprotein, CD44s, CD44v5 and CD44v6. Other parameters considered were clinical stage, lymph node involvement, histological grade (HG), ploidy and the cellular S-phase fraction measured by flow cytometry on nuclei obtained from fresh tissues. In the 95 squamous cell carcinomas the cytosolic levels of NSE varied from 4.5 to 2235 ng/mg protein (median: 267) and were significantly higher (p < 0.001) than those observed in 38 samples of normal pulmonary tissue obtained from the same patients (range: 56-657; median: 141.5). When classifying tumors according to the different parameters analyzed, we observed that the levels of NSE were higher in aneuploid than in diploid cases (p = 0.046) and in those that were HG3 than in those that were HG2 (p < 0.001). Tumors with high NSE levels (> 422 ng/mg protein; 75th percentile) were more likely to have high S-phase values (p = 0.012) and were more frequently aneuploid (p = 0.038) and HG3 (p < 0.001) than those with low levels of NSE (< 180 ng/mg protein; 25th percentile). These results lead us to the following conclusions: 1) the cytosolic concentrations of NSE are significantly higher in squamous cell carcinomas than in healthy pulmonary tissue, and 2) the cytosolic concentrations of NSE are not correlated with clinical stage or nodal involvement. However, in our study higher levels of the enzyme were statistically correlated with aneuploidy, histological grade 3 and S-phase. This may explain its association with poorer outcome and progression, but also the more favorable response of tumors with elevated NSE to chemotherapy, as suggested by other groups.

Medication and fitness to drive.

PURPOSE: The aim of this study is to analyze the consumption patterns of medicaments among motor vehicle drivers who attend 'Medical Driving Test Centres' and the relation between habitual consumption of medicaments and fitness to drive. METHODS: The study was carried out on 8043 drivers who attended 25 Medical Driving Test Centres. RESULTS: 24.7% of drivers chronically consume medicaments while 6.8% consume medicaments along with alcohol every day. Of those who chronically consume medicaments with a warning about the medications on driving, 65.8% were considered 'fit' to drive, 27.3% 'fit with restrictions', 5.1% 'suspended' and 0.4% 'unfit'. CONCLUSIONS: The results show how frequent the consumption of medicaments along with alcohol is and that the great majority of drivers who take medicaments are considered fit to drive.

[Estimating the costs associated with nosocomial urinary tract infection. A case-control study]. / Estimación de los costes asociados a la infección urinaria nosocomial. Un estudio de casos y controles.

BACKGROUND: Nosocomial infection (NI) is associated with increased resource use. The current study addressed the cost excess attributable to nosocomial urinary tract infection (NUTI). METHODS: Case-control study conducted in a cohort population. For matching, the Diagnostic Related Group (DRG) to which the episode of case patient was ascribed was used. Then, a further search was conducted in the hospital discharge database with the following parameters: DRG, gender, age, admission date, department, comparison of length of stays, main diagnosis, co-morbidities, number of secondary diagnoses and procedures. Matching was achieved for 64 episodes (71%), and upon them an estimation of costs was performed. RESULTS: The mean length of stay for cases were 15.3 (median: 12) and 12.3 (median: 11) days for cases and controls, respectively (p = 0.0001). The excess of length of stay attributable to NUTI was 3 days (95% CI 1.6-4.7), longer for patients admitted to Medical Departments (5.3 days) than for patients admitted to Surgical Departments (2 days) (p = 0,03). The use of diagnostic resources was significantly higher for bacteriological testing only. The use of antibiotics and fluid therapy was higher among infected patients. Out of the total excess of the estimated costs per episode, 132,047 ptas, 93% corresponded to the increase in hospital stay. Ten patients (15.6%) were responsible for 68% of the total of extra-costs. In 17 occasions (26.6%), the control patient used more resources than the infected patient. CONCLUSIONS: Nosocomial urinary tract infection is associated with a resource use directly related to its presence. For the most part, it is related to the prolongation of hospital stay.

[CD44s Cell surface expression in 55 lung adenocarcinomas. Negative correlation with tumor size and CA125 cytosolic levels]. / Estudio de la expresión de CD44s en 55 adenocarcinomas pulmonares. Correlación inversa con el tamaño y las concentraciones citosólicas de CA125.

INTRODUCTION: CD44s belongs to a family of cell adhesion molecules involved in cell adhesion, migration and cell-extracellular matrix interactions. In this work we attempt to study CD44s expression in lung adenocarcinomas and its possible correlation with other clinicobiological parameters. MATERIAL AND METHODS: Using an EIA, cell surface CD44s levels were determined in 55 lung adenocarcinomas, classified according to clinical stage, histological grade, ploidy and cellular S-phase fraction. CA125 cytosolic concentrations were also assayed. RESULTS: Forty two adenocarcinomas (76.4%) showed CD44s concentrations > 80 ng/mg prot, and did not differ significantly from those observed in 16 normal samples (93.7%). There were no differences in CD44s expression when clinical stage (I: 24/28, II: 6/9 and III: 12/17), lymph node involvement (N = 245/29, N+: 18/26), ploidy (diploid: 3/5, aneuploid: 32/39), histological grade (I: 6/7, III: 18/26) and cellular S-phase (> 8.8%: 24/31, < or = 8.8%: 17/24) were considered. Positive CD44s tumors had lower CA125 (p: 0.0072) cytosolic levels and a reduced tumor size (p: 0.0093). CONCLUSIONS: CD44s expressions in lung adenocarcinomas did not correlate with any clinicobiological parameters, but there was a negative correlation between this and reduced tumor size and lower CA125 cytosolic levels.

Estimación de los costes asociados a la infección urinaria nosocomial. Un estudio de casos y controles / Estimating the costs associated with nosocomial urinary tract infection. A case-control study

Fundamento. La infección nosocomial (IN) se acompaña de un incremento en el consumo de recursos. En el presente estudio se estima el exceso de costes atribuible a la infección urinaria nosocomial (IUN).Métodos. Se realizó un estudio de casos y controles anidado en un estudio de cohortes. Para el apareamiento se partió del Grupo Relacionado con el Diagnóstico (GRD) al que se adscribió el episodio del paciente caso, con una búsqueda ulterior en la base de datos de altas hospitalarias utilizando las siguientes variables: GRD, sexo, edad, fecha de ingreso, servicio, comparación de estancias, diagnóstico principal, comorbilidad, número de diagnósticos secundarios y procedimientos. Se logró el apareamiento en 64 episodios (71 por ciento), sobre los que se realizó la estimación de costes. Resultados. La estancia media fue para los casos de 15,3 días (mediana: 12) y para los controles de 12,3 días (mediana: 11); p = 0,0001. El exceso de estancia atribuible a la IUN fue de 3 días (IC 95 por ciento: 1,6-4,7), mayor para los pacientes ingresados en los servicios médicos, 5,3 días, que en aquellos que sufrieron intervenciones quirúrgicas, 2 días; p = 0,03. El consumo de recursos diagnósticos fue significativamante más elevado únicamente en pruebas bacteriológicas. El consumo de antibióticos y fluidoterapia fue mayor en los pacientes infectados. Del exceso total del coste estimado por episodio, 132.048 pesetas, el 93 por ciento corresponde al incremento de estancias. Diez pacientes (15,6 por ciento) fueron responsables del 68 por ciento del total de costes extras. En 17 ocasiones (26,6 por ciento) el paciente control consumió más recursos que el paciente infectado. Conclusiones. La infección urinaria nosocomial se acompaña de un consumo de recursos directamente relacionado con su existencia. En su mayor parte está relacionado con la prolongación de la estancia hospitalaria (AU)

[CYFRA 21.1 cytosol levels in lung adenocarcinomas. Correlation with other clinico-biological parameters]. / Estudio de las concentraciones citosólicas de CYFRA 21.1 en adenocarcinomas de pulmón, correlación con otros parámetros clinicobiológicos.

INTRODUCTION: Cyfra 21.1 are soluble cytokeratin 19 fragments present in several biological fluids. The aim of this work was to study cyfra 21.1 cytosolic levels in lung adenocarcinomas and their possible correlation with other clinical-biological parameters. PATIENTS AND METHODS: Cyfra 21.1 was determined, using an immunoradiometric assay (CIS BioInternational. France), in 58 tissue samples of lung adenocarcinomas patients. Other parameters included in the study were the following: clinical stage, histological grade, ploidy, S-phase cellular fraction, as well as cathepsin D, CA 125 and hyaluronic acid levels in cytosols. Likewise, AH, erbB2 oncoprotein, CD44s, CD44v5 and CD44v6 levels in cell surfaces were assayed. RESULTS: Cyfra 21.1 cytosolic levels oscillated between 24.8 and 6,774 ng/mg prot. (median 1,147.5) and were higher (p:0.00074) than those observed in 16 normal lung samples of the same patients. We did not observe any statistically significant differences in cyfra 21.1 values when clinical stage, ploidy, S-phase and histological grade were considered. When lung adenocarcinomas were classified according to cyfra 21.1 positivity, using 1,499 ng/mg prot. as cut-off, which represents the 75th percentile of the whole group, we noted that positive cases had higher levels of cathepsin D (p:0.00218), cytosolic hyaluronic acid (p:0.02947), erbB2 protein (p:0.06272) and CA 125 (p:0.07243) than negative carcinomas. CONCLUSIONS: These results suggest the possibility that high cytosolic cyfra 21.1 levels could be associated with a poor outcome in lung adenocarcinomas.