The E-cadherin cell–cell adhesion complex and lung cancer invasion, metastasis, and prognosis
Introduction
Lung cancer is the leading cause of cancer death in developed countries. Due to the lack of diagnostic tools for early detection and of efficient treatment for advanced disease, the prognosis of lung cancer is still poor, with less than 15% surviving 5 years after diagnosis [1]. Among patients treated for early (T1-2N0M0) non-small cell lung cancer (NSCLC) and considered postoperatively tumour-free, about 40% will relapse within 2 years after surgery and subsequently die of metastatic spread [2], [3]. Hitherto, detailed histopathological examinations and clinical prognostic factors have been of limited value in predicting lung cancer outcome. Recently, advances in molecular biology and pathology have led to a better understanding and documentation of the molecular and morphological changes during lung cancer carcinogenesis [4]. These advances may provide a basis for earlier detection and improved treatment of lung cancer.
In different species, biologists have shown that cell and organ development, which exhibit many similarities with carcinogenesis, basically is encoded for by a handful of signaling pathways, including the Wnt/frizzled pathway [5]. Mutations of genes encoding some elements of each of these pathways have emerged as oncogenes (dominant active version of the protein) or as tumour suppressor genes (revealed as recessive mutations).
The study of cell and organ development has provided important insights into the causes of cancer. What once was a catalogue of functionally diverse proteins associated in puzzling ways is now beginning to gel into a picture of a few defined molecular events that are common to all malignant cells [6]. These events are: (1) self-sufficiency in growth signals; (2) insensitivity in growth inhibitory signals; (3) evasion of programmed cell death; (4) limitless replicative potential; (5) sustained angiogenesis; and (6) tissue invasion and metastasis. These six alterations in cell physiology are common to most cancers [6]. Tissue invasion and metastasis are common features of the most aggressive and lethal tumours and require that cells loose contacts with the neighboring cells. These tumour cells become motile, invade the surrounding territories, migrate, enter the circulation, extravasate into the target organ, and proliferate [7].
It has been known for more than 40 years that cancer cells commonly show decreased intercellular adhesiveness when compared with corresponding normal epithelium [8]. Today we know that cells' acquisition of motile properties correlates with a loss of its ability to recognise with and adhere to its neighbors. An important group of molecules involved in these events is cadherins. Their function is again dependent on the integrity of four intracellular catenins. Together these molecules constitute the cadherin–catenin cell–cell adhesion complex, which plays a critical role in the pathogenesis of human carcinomas [9], [10], [11].
Recently, several investigators have reported that reduced expression of the cadherin adhesion complex in lung cancer cells is associated with dedifferentiation, increased invasiveness, metastasis, and poorer survival [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. In the following, we will give an insight into the role of the cadherin–catenin adhesion complex in normal and malignant tissues, evaluate the consequences of altered expression of this complex in lung cancer, and discuss its possible therapeutic implications in the future.
Section snippets
E-cadherin and the cadherin family
There are four groups of cell adhesion molecules (CAMs) involved in cell–cell and cell–matrix adhesion, of which the cadherins are considered the most important. The other CAMs are integrins, the immunoglobulin superfamily, and selectins [9], [26]. Cadherins are single transmembrane proteins that mediate cell–cell adhesion in a strictly Ca2+ dependent manner, and have been divided up into more than 10 subgroups, depending on their tissue distribution. These groups include E- (epithelial), N-
Role of the catenins in signal transduction pathways
For years, studies on β-catenin, first discovered as a link between cadherins and the cytoskeleton, provided a complement to those of cadherins. But the finding that the Drosophilia β-catenin homologue, Armadillo, plays a central role in Wnt signaling modified the view of this molecule's function from a structural role in cell adhesion to a dynamic, active role in the control of gene expression in cancer and development [60], [61], [62], [63] (Fig. 2). In vertebrates, Wnt is known as a
The E-cadherin–catenin adhesion complex and cancer
Since an intact E-cadherin adhesion complex is required for maintenance of normal intercellular adhesion, several investigators have proposed E-cadherin as an invasion suppressor molecule in carcinoma cells. Furthermore, a delicate balance of the catenins seems essential for normal cell functions. Recently, it has been clear that E-cadherin also has a growth suppressor function by inducing cell cycle arrest via upregulation of the cyclin-dependent kinase, p27 [84], [85].
E-cadherin and catenin
Association between the E-cadherin–catenin adhesion complex and lung cancer pathology, stage, and survival
For several non-pulmonary neoplasms, clinical studies have demonstrated that aberrant expression of E-cadherin, α-, β-, and γ-catenin, and p120 is associated with histopathological tumour characteristics (differentiation, invasiveness, and venous permeation), tumour stage, regional and distant metastasis, disease relapse, and survival [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120]. More recently,
The E-cadherin–catenin complex: a possible target for anticancer therapy?
Hitherto, advanced lung cancer is considered incurable and even the survival of patients with resectable NSCLC is poor [2], [3]. The persistent grim lung cancer outcome argues for new approaches to control this disease, aimed at early stage lung cancer and chemoprevention in high-risk individuals with preneoplastic changes. It has been suggested that future directions for lung cancer chemoprevention should include studies of molecular markers in carcinogenesis and molecular targeting trials
Conclusion
The E-cadherin–catenin complex serves as a cell–cell adhesion complex and in part as an intracellular signal transducer. The complex is up- and down-regulated at various levels and by various agents, reversibly or permanently. From experimental data we know that this complex has a cancer invasion suppressor function, and is frequently downregulated in malignant tumours. Moreover, data from clinical lung cancer studies have demonstrated a significant association between downregulation of this
Acknowledgments
Supported by research grants from the National Cancer Institute [SPORE in lung cancer (P50-CA58187) and Early Detection Research Network (EDRN, U01-CA15070)]; The Norwegian Cancer Society, Oslo, Norway (R.M. Bremnes); International Association for the Study of Lung Cancer/Cancer Research Foundation of America (F.R. Hirsch).
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