Elsevier

European Journal of Cancer

Volume 42, Issue 14, September 2006, Pages 2382-2389
European Journal of Cancer

Role of prostaglandin E2 in the invasiveness, growth and protection of cancer cells in malignant pleuritis

https://doi.org/10.1016/j.ejca.2006.03.022Get rights and content

Abstract

The recurrence of pleural effusions is a common event in a variety of neoplastic diseases. The objective of this study was to identify the mechanisms promoting the homing and growth of cancer cells within the pleural space. A cancer cell line recovered from malignant pleural fluids (lung adenocarcinoma cell line) that constitutively expresses cyclooxygenase 2 (COX-2) and all types of prostaglandin receptors was studied. It was first demonstrated using a matrigel system, that malignant pleural fluids increase the invasiveness of adenocarcinoma cells more than congestive heart failure (CHF) pleural fluids. Moreover, exposure to exudative malignant, but not to CHF pleural fluids, increased the mRNA (measured by real-time polymerase chain reaction (PCR)) and protein expression of COX-2 (measured by Western blot), as well as the activation and nuclear translocation of nuclear factor κB (NFκB) in cancer cells. These events are all actively regulated by prostaglandin E2 (PGE2), since the addition of synthetic PGE2 to cancer cells and the depletion of PGE2 from malignant pleural fluids or the inhibition of COX-2 activity significantly increased and reduced these phenomena, respectively. Moreover, malignant pleural effusions and synthetic PGE2 increased the long-term proliferation of cancer cells and reverted the impairment in long-term proliferation due to talc exposure. This study demonstrates that PGE2 present in malignant effusions contributes to cancer expansion and may protect cancer cells by anti-proliferative effects induced by talc.

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.

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