Prognostic significance of pS2 protein expression in pulmonary adenocarcinoma

doi:10.1016/0959-8049(94)90294-1

European Journal of Cancer

Volume 30, Issue 6, 1994, Pages 792-797

https://doi.org/10.1016/0959-8049(94)90294-1 Get rights and content

Abstract

In the present study, pS2 protein expression in pulmonary adenocarcinoma was investigated on paraffin-embedded sections obtained from 170 patients. 28 (16%) patients showed varying degrees of pS2 protein expression in the cytoplasm of tumour cells, as detected by immunohistochemical staining with anti-pS2 protein antibody. There was a significant association between pS2 protein expression and larger tumour size, and the acinar or bronchiolo-alveolar subtype. However, no significant correlations between pS2 protein status and the other clinicopathological factors, i.e. T-factor, N-factor, stage and histological differentiation, were shown. In contrast to breast cancer, patients with pS2-positive pulmonary adenocarcinomas had a significantly worse prognosis than those with pS2-negative pulmonary adenocarcinomas; this was true for stage I patients, as well as for all patients. Multivariate analysis showed that pS2 protein expression was a discriminating variable in overall survival. These findings suggest that pS2 protein status is a possible prognostic indicator in pulmonary adenocarcinoma.

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Cited by (23)

Trefoil factors (TFFs) are increased in bronchioalveolar lavage fluid from patients with chronic obstructive lung disease (COPD)
2015, Peptides
Citation Excerpt :
Forty percent of small cell lung cancers and carcinoid lung tumors have positive TFF1 immunostaining [46]. Expression of TFF1 by a pulmonary tumor is associated with a poor prognosis, possibly linked to increased expression of CA125 and decreased expression of the EGF-receptor [11]. TFF1 is elevated in serum in advanced stages of adenocarcinomas and bronchoalveolar carcinomas and it is normalized after removal of the tumor [12].
Trefoil factors (TFFs) 1, 2 and 3 are small polypeptides that are co-secreted with mucin throughout the body. They are up-regulated in cancer and inflammatory processes in the gastrointestinal system, where they are proposed to be involved in tissue regeneration, proliferation and protection. Our aim was to explore their presence in pulmonary secretions and to investigate whether they are up-regulated in pulmonary diseases characterized by mucin hypersecretion. Bronchioalveolar lavage fluid was obtained from 92 individuals referred to bronchoscopy. The patients were grouped according to diagnosis and pulmonary function. The concentrations of TFF1, TFF2 and TFF3 were measured by ELISA. All three peptides were detected in bronchioalveolar lavage fluid. Patients with chronic obstructive pulmonary disease had concentrations two to three times above the levels in the healthy reference group, and patients with pulmonary malignancies had concentrations of TFF1 and TFF2 three times that of the reference group. The results suggest that TFFs are involved in tissue regeneration, proliferation and protection in lung diseases.
Are trefoil factors oncogenic?
2008, Trends in Endocrinology and Metabolism
Citation Excerpt :
TFF expression has been described in a variety of other cancers. The serum level of TFF1 is increased in patients with lung adenocarcinoma and reduced after tumour resection [66], and patients with TFF1 protein-positive pulmonary adenocarcinomas had a much worse prognosis than those with TFF1-negative adenocarcinomas [67]. TFF1, TFF2 and TFF3 mRNA expression has been associated with pancreatic cancer [3,6,68,69], with all three family members identified as the most markedly upregulated genes in intraductal papillary-mucinous tumours of the pancreas [3,6].
Trefoil factors (TFFs), in particular TFF1, are classical estrogen-regulated genes and have served as markers of estrogen gene regulation by various environmental estrogens. TFFs are also regulated by several other factors including growth hormone (hGH), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF) and various oncogenic stimuli. TFFs are secreted proteins present in serum and possess the potential to act as growth factors promoting cell survival, anchorage-independent growth and motility. Recent compelling evidence has emerged from experimental and clinical studies to indicate a pivotal role of TFFs in oncogenic transformation, growth and metastatic extension of common human solid tumours. This review will summarize the current evidence for the involvement of TFFs in human cancer.
CA125 cytosolic levels in lung adenocarcinomas. New biological aspects
2005, Revista Espanola de Medicina Nuclear
El CA125 sérico es útil marcador de los carcinomas no mucinosos de ovario, pero puede incrementarse en otros tumores, entre los cuales están los no microcíticos de pulmón. Nosotros hemos querido estudiar, en adenocarcinomas pulmonares, su concentración citosólicas y correlacionarlas con la pS2, CD44s, CD44v5 y CD44v6, todas ellas con interés fisiopatológico en aquellos tumores.
El grupo estudio incluyó 55 pacientes (33 varones) afectos de adenocarcinomas pulmonares. El CA125 y la pS2 citosólicos fueron determinados mediante sendos IRMAS (CIS. Biointernational.Francia), mientras que las concentraciones de CD44s, CD44v5 y CD44v6 en las membranas celulares fueron dosificadas mediante EIAS (Bender Diagnostics. Austria). Otros parámetros considerados fueron el estadio clínico, ploidía y la fase de síntesis celular.
Las concentraciones citosólicas de CA125 oscilaron entre 1 y 225 U/mg prot. (mediana 80.5) y fueron superiores (p: 0,002) a las observadas en 16 muestras de tejido pulmonar normal de los mismos pacientes (i:1-32,5; mediana 6,7 U/mg prot.). Cuando los adenocarcinomas fueron clasificados en función de la concentración de CA125, tomando como dinteles los percentiles 25 (7,2 U/mg prot.) y 75 (320 U/mg prot.), pudimos observar que los tumores con altos valores antigénicos mostraron mayor positividad para el CD44v6 (p: 0,002) y menor para el CD44s (p: 0,053); asimismo, tuvieron tendencia a ser más frecuentemente pS2 + (p: 0,09).
Los resultados anteriores nos inducen a las siguientes consideraciones: 1) en los adenocarcinomas pulmonares las concentraciones citosólicas de CA125 son superiores a las constatadas en el tejido pulmonar normal de los mismos pacientes; 2) los adenocarcinomas pulmonares con altas concentraciones de CA125 presentan una mayor positividad para el CD44v6 y menor para el CD44s, mostrando, además, una tendencia a ser más frecuentemente pS2 +. Todo ello apoya su interés como indicador de un peor pronóstico en este subtipo histológico pulmonar.
CA125 is a useful serum tumor marker in patients with non-mucinous ovarian cancer, but there may be high serum levels in other malignant tumors, among them the non-small cell lung cancers. We decided to study the cytosolic levels of CA125 in lung adenocarcinomas and compare them with pS2, CD44s, CD44v5 and CD44v6, all of them with biological interest in this subtype of lung carcinomas.
The study group included 55 patients (33 males) having lung adenocarcinomas. CA125 and cytostolic pS2 were measured by both IRMAS methods (CIS. Biointernational. France). The concentrations of CD44 standard (CD44s), CD44v5 and CD44v6 on cell surfaces were dosed by EIAS (Bender Diagnostics. Austria). Clinical stage, ploidy and S-phase cellular fraction were also taken into account.
In the 55 lung adenocarcinomas, cytosolic CA125 levels ranged between 1 and 225 U/mg prot. (median 80.5) and were higher (p:0.002) than those observed in 16 normal lung tissues from the same patients (r: 1-32.5; median 6.7 U/mg prot.). When the 25^th (7.2 U/mg prot.) and 75^th (320 U/mg prot.) percentiles were used as clinical cut-offs, we found that the cases with high antigenic levels showed a greater positivity for CD44v6 (p:0.002) and a reduced positivity for CD44 standard (p:0.053). Likewise, they showed a tendency towards being pS2 + (p:0.09) more frequently.
Our results lead us to draw the following conclusions: 1) Cytosolic CA125 levels in lung adenocarcinomas were higher than those observed in normal tissues from the same patients. 2) Lung adenocarcinomas with high cytosolic CA125 concentrations had a greater positivity for CD44v6, a reduced positivity for CD44s and were more frequently pS2 +. These associations support the usefulness of the cytosolic CA125 levels as an indicator of poor outcome in this subtype of lung carcinomas.
Cytosolic pS2 levels in 154 non small cell lung carcinomas. Correlation with other clinical and biological parameters
2002, Revista Espanola de Medicina Nuclear
—Introducción: La pS2 es una proteína inducida por los estrógenos, factores de crecimiento y ciertas proteínas oncogénicas, cuya principal aplicación clínica reside en los tumores mamarios, donde es un indicador de la hormonodependencia. Nosotros hemos querido analizar su comportamiento en carcinomas pulmonares no microcíticos, correlacionando los resultados con los observados en tejidos normales y con otros factores clínico-biológicos que podrían ayudar a precisar su valor práctico.
El grupo estudio incluyó 154 carcinomas no microcíticos de pulmón (59 adenocarcinomas y 95 carcinomas escamosos) y 54 muestras pulmonares normales. En el citosol determinamos las concentraciones de pS2, catepsina D, enolasa específica neuronal y CA125, mientras que en las membranas celulares dosificamos el receptor del factor de crecimiento epidérmico (EGFR), proteína erbB2, CD44s, CD44v5 y CD44v6. Se consideró asimismo el estadío clínico, grado histológico, ploidia y fase de síntesis celular.
Cifras de pS2 citosólico superiores a 1 ng/mg proteína (dintel de positividad) se observaron en 18/59 adenocarcinomas y en 10/95 carcinomas escamosos (p:0,00177). En los adenocarcinomas la positividad para la pS2 no se correlacionó con ningún parámetro clínico-biológicos, pero los casos positivos cursaron con menores concentraciones de EGFR (p:0,03770) y mayores de CA 125 (p:0,01902). En los carcinomas escamosos, la positividad para la pS2 se asoció a menores concentraciones de EGFR (p:0,02270) y mayores de proteína erbB2 (p:0,00563).
Los resultados anteriores nos inducen a las siguientes consideraciones: 1) las concentraciones citosólicas de pS2 son mayores en los tumores que en las muestras normales; 2) los adenocarcinomas cursan con mayores concentraciones y positividades para la pS2 que los carcinomas escamosos; 3) en los adenocarcinomas la positividad para la pS2 no se correlacionó con ningún parámetro clínico, pero sí con menores concentraciones de EGFR y mayores de CA125, lo que sugiere la posibilidad de que sea indicador de un peor comportamiento y 4) en los carcinomas escamosos, la positividad para la pS2 se asoció con menores concentraciones de EGFR y mayores de proteína erbB2, sin que podamos precisar su significado clínico, aunque posiblemente refleje un mejor comportamiento.
—Introduction: pS2 was first identified as an estrogen induced molecule in a breast cancer cell line, but its gene responds to several growth factors and oncogenic proteins. Its main clinical application lies in breast carcinomas, where it is a molecular marker to identify breast cancer patients who will respond to hormone therapy. This study was performed to evaluate the significance of the pS2 cytosolic levels in non small cell lung carcinomas classified according to different clinical and biological parameters. Likewise, the results obtained were correlated with those observed in normal tissues.
The study group included 154 non small cell lung carcinomas (59 adencarcinomas and 95 squamous carcinomas) and 54 normal lung samples. Cathepsin D, pS2, neuron specific enolase (NSE) and CA125 cytosolic concentrations were determined, as well as those of epidermal growth factor receptor (EGFR), erbB2 protein, CD44s, CD44v5 and CD44v6 on cell surface membranes. Likewise, clinical stage, histological grade, ploidy and cellular S-phase fraction were also considered as variables of the study.
We observed cytosolic pS2 values greater than 1 ng/mg protein (positive cutoff) in 18/59 adenocarcinomas and in 10/95 squamous carcinomas (p:0.00177). In adenocarcinomas, pS2 positivity was not correlated with any clinical and biological parameters, but positive cases had lower EGFR (p:0.03770) concentrations and higher CA125 (p:0.01902) levels. In squamous carcinomas, pS2 positivity was asociated with lower EGFR (p:0.02270) levels and higher erbB2 protein (p:0,00563) concentrations.
Our results led us to suggest the following: 1) cytosolic pS2 concentrations are higher in tumoral than in normal samples; 2) adenoarcinomas had higher levels than squamous lung carcinomas; 3) in adenocarcinomas, positivity for pS2 is associated with lower EGFR levels and higher CA125 concentrations suggesting a worse outcome, and 4) in squamous lung tumors, positivity for pS2 was associated with lower EGFR and higher erbB2 oncoprotein concentrations, it not being possible to establish its clinical significance, although it may be correlated with a poor prognosis.
DNA hypermethylation at the pS2 promoter region is associated with early stage of stomach carcinogenesis
2000, Cancer Letters
pS2, a member of the trefoil peptide family, has been suggested to be a gastric-specific tumor suppressor. We examined the expression of pS2 in gastric carcinomas, adenomas and non-neoplastic mucosa and analyzed the DNA methylation in the pS2 promoter. Reduced expression of pS2 was frequently associated with well-differentiated adenocarcinomas. The CpG sites within the promoter region of the pS2 gene were methylated in pS2-negative gastric carcinoma cell lines whereas it was not in pS2-positive cell line. The promoter methylation was detected in gastric carcinoma tissues and intestinal metaplasia with reduced pS2 expression whereas none of the carcinomas with preserved pS2 expression showed the promoter methylation. These findings suggest that reduced expression of pS2 due to the promoter methylation may participate in an early stage of stomach carcinogenesis, especially of well differentiated type.
The pS2/TFF1 trefoil factor, from basic research to clinical applications
1998, Biochimica et Biophysica Acta - Reviews on Cancer
pS2/TFF1 trefoil factor is normally expressed in the stomach, and is found ectopically in gastrointestinal inflammatory disorders and in various carcinomas. It is involved in stomach ontogenesis and in the maintenance of the integrity of the mucosa, and may represent a pharmacological tool for prevention and healing of gastrointestinal ulcerations. In breast cancer, it can be used to select patients suitable for hormone therapy. pS2/TFF1 is a pleiotropic factor involved in mucin polymerization, cell motility, cell proliferation and/or differentiation, and possibly in the nervous system.

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PaperPrognostic significance of pS2 protein expression in pulmonary adenocarcinoma

Abstract

Cell

Eur J Cancer

Eur J Cancer

Biochem Biophys Res Commun

FEBS Lett

Reg Pept

FEBS Lett

Gastroenterology

Cloning of cDNA sequences of hormone regulated genes from the MCF-7 human breast cancer cell line

Nucleic Acids Res

Sequence of the pS2 mRNA induced by estrogen in human breast-cancer cell line MCF-7

Nucleic Acids Res

Specific expression of the pS2 gene in subclasses of breast cancers in comparison with expression of the estrogen and progesterone receptors and the oncogene ERBB2

Regulation of cathepsin-D and pS2 gene expression by growth factors in MCF7 human breast cells

Mol Endocrinol

Prediction of relapse and survival in breast cancer patients by pS2 protein status

Cancer Res

pS2 expression and response to hormonal therapy in patients with advanced breast cancer

Cancer Res

Antipeptide antibodies against the pNR-2 oestrogen-regulated protein of human breast cancer cells and detection of pNR-2 expression in normal tissues by immunohistochemistry

J Pathol

Paper
Prognostic significance of pS2 protein expression in pulmonary adenocarcinoma