ReviewThe role of cell adhesion molecules in the progression of colorectal cancer and the development of liver metastasis
Introduction
Colorectal cancer (CRC) is the third most common malignancy worldwide and the second cause of cancer death in North America and Western Europe. It primarily affects people of advanced age, as the majority of cases are diagnosed in individuals over 50 and half of them are older than 70 years of age [1], [2]. The prognosis and the overall survival is mainly determined by the progression of liver secondary disease and not by the primary carcinoma, even in patients with an isolated hepatic tumour. If liver metastases remain untreated, life expectancy is less than a year [3].
The maintenance, promotion or disruption of cell adhesion are particularly important processes in CRC progression and metastasis. Multiple cell adhesion molecules (CAMs) are implicated not only in malignant cell detachment from the primary carcinoma, but also in tumour cell attachment to distant tissue (Table 1). In the former case, adhesion is downregulated, mainly by modification of the cadherin–catenin system; in the latter, cell surface molecules mediate the tumour–host attachment [4]. Interestingly, CAMs may also regulate the organ selectivity of metastasis, through their altered expression on various epithelia and the presence of different adhesion ligands on various CRC cell lines [5], [6].
The hepatic colonization initiates in the sinusoids, where sinusoidal endothelial cells (SECs), Kupffer and stellate cells interact with the invaders, expressing a variety of CAMs and their receptors [7]. Moreover, multiple signalling molecules such as focal adhesion kinase, paxillin, and cytoskeletal proteins, like actin and microtubules, are also required for tumour cell adhesion and stabilisation under the hydrodynamic conditions of blood flow [8]. Successful attachment to the sinusoidal endothelium enables colorectal cells to extravasate, invade the hepatic parenchyma, mainly via proteolytic action, and create metastases [9], [10], [11].
Section snippets
Cadherin–catenin system
Cadherins are single pass transmembrane glycoproteins which serve as calcium-dependent adhesion receptors and present extracellular cadherin repeats. Their large family includes more than 19 molecules of approximately 120 kDa, such as classical cadherins (homophilic adhesion molecules), protocadherins, desmogleins and desmocollins. Different classical cadherins are expressed in various tissues and according to location they are termed E-, N-, P- and VE-cadherin [12], [13], [14]. E-cadherin
Immunoglobulin superfamily cell adhesion molecules (IgSFCAMs)
The immunoglobulin superfamily consists of numerous cell surface and soluble proteins, involved in intercellular recognition, binding and adhesion. Among its multiple subgroups, it includes antigen receptors, growth factors and cytokine receptors (e.g. PDGFR, IL-1β and IL-6 receptor), antigens of tumour cells (e.g. CEA), T-lymphocyte and natural killer cell receptors (e.g. CD4) and cellular adhesion molecules [54]. IgSFCAMs represent one of the most ancient and diverse groups of cell adhesion
Selectins
Selectins comprise a family of three cell adhesion molecules: E-selectins, present exclusively in endothelial cells, P-selectins in platelets and endothelial cells and L-selectins in leukocytes. Their structure is similar, with 5 domains: c-type lectin, epidermal growth factor like, complement binding, transmembrane and a small intracellular domain (cytoplasmic tail) (Fig. 3). The transmembrane domain anchors selectins to the membrane and the cytoplasmic tail supports their action as signalling
Integrins
Integrins are heterodimer cell surface receptors which interact with the ECM and regulate intracellular communication via outside-in and inside-out signalling. They are composed of α and β transmembrane subunits and each of them includes a large extracellular, transmembrane and short cytoplasmic domain. In mammals, 19 α and 8 β subunits combine with each other to form a family of 24 cell adhesion molecules. While several subunits may occur only in a single integrin, others are present in
Conclusions and future perspectives
Cell adhesion molecules play an important role in the progression of colorectal cancer and its metastatic migration to the liver. Multiple cytokines, growth factors and cell populations, such as endothelial, epithelial, immune, and blood cells as well as platelets interact, express and/or secrete CAMs. These molecules are present either in the primary or metastatic sites, following molecular pathways and mechanisms, which are usually not well-defined.
The sinusoids are the entrance gate for
Acknowledgements
The authors would like to express their gratitude to Professor A.W. Majeed, consultant hepatobiliary surgeon, member of the Liver Research Group, for reviewing the manuscripts.
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