Role of prostaglandin E2 in the invasiveness, growth and protection of cancer cells in malignant pleuritis
Introduction
Malignant pleural effusions recur in 15% of patients who die with malignancies, account for up to 50% of the exudates in many clinical series,1 and are related to a primary tumour (mesothelioma) or, more frequently, to metastatic adenocarcinoma tumours of lung, ovarian, gastrointestinal or breast origin. Tumour invasion of the pleural compartment activates multiple biological mechanisms, which result in the accumulation of fluid enriched in proteins in the pleural space (i.e. the development of an exudative pleural effusion).1, 2 Although the recurrence of a malignant pleural effusion is a common event, the mechanisms of tumour localisation into the pleura, as well as the mechanisms propelling the growth of metastases within the pleura, are not well elucidated.1
Recent studies have further elucidated the long-recognised relationship between the pathological processes of infection, inflammation and cancer.3 Inflammation promotes the first stage of neoplastic transformation, also known as ‘initiation’, as well as tumour growth, by stimulating cell proliferation, adhesion, vascularisation and by increasing the metastatic potential of later stage tumours. However, little is known about the contribution of inflammation to the ‘homing’ of cancer cells in particular metastatic sites and to the growth of metastatic cells in the new compartments.
Previous studies, concerning a variety of tumours, have implicated the expression of cyclooxygenase 2 (COX-2) in different steps of tumour genesis, including tumour invasiveness4 and cancer cell proliferation and resistance to apoptosis.5, 6 One of the best-known and most well-studied metabolites due to COX-2 activation is prostaglandin E2 (PGE2).5 PGE2 is produced by a variety of cells, including macrophages and some types of malignant cells, and exerts its activities close to the site of production by binding to one or to a combination of four subtypes of receptor (EP1, EP2, EP3 and EP4).5 This mediator regulates immunity and inflammation and plays an emerging and crucial role in cancer progression. The inhibition of COX-2 in human head and neck cancer results in loss of intra-tumour PGE2 levels and in turn leads to a reduced proliferation and to increased apoptosis of cancer cells.7 Moreover, PGE2 inhibits cytotoxic activity of monocytes against cancer cells by decreasing the release of tumour necrosis factor-α (TNF-α).8
The present study was performed: (i) to assess whether malignant pleural fluids contain soluble factors able to promote the ‘homing’ of lung adenocarcinoma cancer cells within the pleural space; (ii) to address whether malignant pleural fluids contain soluble factors able to increase COX-2 expression in cancer cells within the pleural space; (iii) to evaluate the contribution of PGE2 to cancer invasiveness and cancer growth within the pleural space. The results show that the release of PGE2 during pleural malignant inflammation actively contributes to cancer ‘homing’ as well as to cancer growth and protection within the pleural compartment.
Section snippets
Pleural fluid collection
Pleural fluids were collected from patients with congestive heart failure (CHF) (n = 6, age range 50–78 years) and cancer (n = 6, age range 41–75 years). All subjects gave informed written consent and the study was approved by the institutional review board for human studies. The effusions were first classified as transudates or exudates by meeting at least one of the criteria described by Light.9 CHF effusions were defined as transudates associated with an enlarged heart, distended neck veins and a
Malignant pleural fluids attract cancer cells
Since the pleura is frequently involved in metastatic neoplastic processes, we first assessed whether pleural fluids from lung cancer patients contained soluble factors promoting the homing of cancer cells within the pleural space. A lung adenocarcinoma cell line was incubated with and without pleural fluids from cancer patients and from CHF patients and the invasiveness of cancer cells was evaluated on the basis of their ability to digest matrigel. Surprisingly, when cancer cells were cultured
Discussion
The diagnosis of a malignant effusion signifies disease progression, and is associated with a worse prognosis regardless of the tumour site of origin.
Although it is well known that specific cancers, such as lung cancer or cancer of the breast, ovary, and stomach preferentially metastasise the pleural compartment,1 the mechanisms that portend a predilection for the pleural compartment are not well elucidated.
This study demonstrates that pleural inflammation generates an ideal micro-environment
Conflict of interest statement
None declared.
Acknowledgement
This work was supported by the Italian National Research Council, Istituto di Biomedicina e Immunologia Molecolare, Commessa di Immunopatologia e Farmacologia delle Malattie Respiratorie.
References (31)
- et al.
Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion
J Biol Chem
(2002) - et al.
Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer
Lancet Oncol
(2001) - et al.
Multifaceted roles of cyclooxygenase-2 in lung cancer
Drug Resist Updat
(2004) - et al.
Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44
J Biol Chem
(2001) - et al.
Increased prostaglandin E2 concentrations and cyclooxygenase-2 expression in asthmatic subjects with sputum eosinophilia
J Allergy Clin Immunol
(2003) - et al.
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
Anal Biochem
(1987) - et al.
Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma
J Allergy Clin Immunol
(2004) - et al.
Adenovirus-uteroglobin suppresses COX-2 expression via inhibition of NF-kappaB activity in lung cancer cells
Lung Cancer
(2005) - et al.
Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase-2
Cell
(1995) - et al.
Management of malignant pleural effusions
Eur Respir J
(2001)
Immunobiology of pleural inflammation: potential implications for pathogenesis, diagnosis and therapy
Eur Respir J
NF-κB: linking inflammation and immunity to cancer development and progression
Nature Rev Immunol
Direct evidence for a role of cyclooxygenase 2-derived prostaglandin E2 in human head and neck xenograft tumors
Cancer Res
Prostaglandin E2 down-regulates the expression of tumor necrosis alpha gene by human blood monocytes
Adv Prostaglandin Thromboxane Leukot Res
Pleural diseases
Dis Mon
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