Adhesive proteins in cancer cells


 
Cell adhesion plays a key role in regulating processes such as cell growth, differentiation and migration. Proteins responsible for the adhesion of so-called CAMs (cellular adhesion molecules) mediate interactions between cells and between cells and the intercellular matrix. To date, more than 50 proteins involved in adhesion have been identified, including: integrins, selectins, cadherins and immunosimilar CAMs-Ig. Each of these protein families has characteristic motifs of structure, as well as different functions performed in cell adhesion, participation in the formation of contact foci, adhesive strips, desmosomes or hemidesmosomes. It should also be mentioned that in the creation of anchored connections, elements of the cellular skeleton are also involved: actin filaments and intermediate filaments.

In normal cells, the correct adhesion process is the basis of such processes as cell movement, intercellular communication or signal transduction. All adhesive proteins are involved to varying degrees in the regulation of cellular processes, recognition of relevant receptors, the process of apoptosis, as well as in the body’s immune response, e.g. during inflammation.

Cancer cells break the basic principles that normal cells are subject to. The main features of cancer cells that enable them to destroy tissue organization are uncontrolled cell division and the ability to bypass programmed cell death or apoptosis. Cancer cells are able to spread throughout the body using two mechanisms:

  • invasiveness, relating to migration within surrounding cells, and
  • metastasis, meaning the ability of cancer cells to penetrate the walls of blood and lymphatic vessels, move to other, often distant tissues and form secondary tumors (malignant, cancer).

Invasiveness and the ability of cancer cells to metastasis is the most serious problem in the fight against cancer. This process is preceded by a loss of integrity and adhesion between cells and the intercellular matrix. In 1944, Coman first noted that there was a visible correlation between altered levels of proteins responsible for adhesion and the ability of cancer cells to invade. The passage of cancer cells into the blood and lymphatic vessels (intravasation) requires the loss of intracellular contacts, which suggests that CAMs are inseparable from the invasion and metastasis of tumors. Furthermore, some viruses use CAM as specific receptors. This sheds new light on adhesive proteins as potential targets for cancer therapy.

Increasing evidence indicates that adhesion abnormalities are an important factor in generating cancer cell invasiveness. Moreover, these features of cancer cells correlate with reduced expression, in particular cadherins. The loss of intracellular contacts due to a decrease in the amount of cadherins, glycoproteins responsible for cell recognition, adhesion and the strength of interactions between cells, creates favorable conditions for invasive cancer cells, enabling them to migrate. Classic cadherins, N-, E-, and P- form the so-called adherence junctions and play various roles in cell-to-cell adhesion . Relocation and reduced cadherin expression correlated with the degree of tumor invasion are observed in various tumor cell lines [1, 5]. E-cadherins appear to be factors that abolish the invasion of cancer cells, as the reconstruction of these adhesion proteins inhibited the metastatic potential of tumors. This is indicated by studies using transgenic mice with pancreatic b-tumor cells (Rip1Tag2 model). As in many human cancers, decreased expression of E-cadherin during transition from primary (benign, adenomas) to malignant (malignant, carcinomas) tumors is also seen in Rip1Tag2 mice. Expression of E-cadherins in pancreatic b cells in transgenic Rip1Tag2 mice resulted in non-invasive tumor arrest (adenomas). This indicates that cadherins not only participate in cell-to-cell adhesion but also, at least indirectly, inhibit tumor growth. Lack of cadherins is one of the factors inducing tumor cell metastasis, probably by transduction of signaling pathways and tumor cell activation factors to invade adjacent cells and tissues. Data indicate that reduced cadherin expression may become a marker of cancer cells of the breast, prostate, intestine and stomach.

Under normal conditions, the extracellular domain of E-cadherin interacts with another, usually the same cadherin on the surface of an adjacent cell. Through catenins, cadherins combine with elements of the actin skeleton, which in effect

This information is only a trace that should be followed to fully understand the interaction of the various pathways in which both adhesion proteins, cellular skzielet proteins and small GTPases are involved, and the involvement of all these factors in cancer cell invasion. The most interesting is how the “disruption” of the adhesive complex between both cells and cells and the extracellular matrix contributes to the acquisition of metastatic potential by cancer cells. Due to the fact that so many adhesion proteins are involved in this process, as well as due to differences in the morphology and functioning of cancer cells resulting from the lack of individual CAMs, a division into “active” and “passive” metastasia has been made (Fig. 1) .

Adhesive proteins in cancer cells
Adhesive proteins in cancer cells

Fig 1. (A) active metastasia associated with the lack of E-cadherins involved in cell-adhesion. (B) passive metastasia is associated with reduced expression of N-CAM (cells of the primary tumor before invasion and metastatic potential pass into the blood vessels and lymphatic cells where they migrate to other tissues) [2].

The invasion of cancer cells into neighboring and distant tissues is facilitated by local proteolysis and dynamic interactions between extracellular matrix receptors, adhesion proteins and the actin skeleton. The main family of ECM receptors are integrins, adhesion proteins that regulate signaling pathways that control the dynamics of the actin cytoskeleton, movement, differentiation and cell growth. It would seem that the level of integrins in cancer cells will be lower compared to normal cells, due to the disruption of connections between cells and ECM (hemidesmosomes) built by integrins. Meanwhile, integrin expression remains at the same level, but they do not form hemidesmosomes, but associate with actin filaments. Integrins in cancer cells are located in lamellia, filopodia and stress fibers, which are created during migration and generating cell movement. Interestingly, integrins are not necessary for the migration of cancer cells. However, their presence clearly increases the metastatic potential of the tumor compared to migrating cells with reduced integrin levels.

In addition, integrins, particularly ╬▒6b4 (alpha-6-beta-4), stimulate phosphoinositol 3-OH kinase (PI3-K). The activity of this enzyme is crucial for the invasion of cancer cells. PI3-K, in turn, activates the Ras suppressor protein, and this entails a series of reactions directly affecting the migration of cancer cells [3]. In fact, the levels of different integrins in different tumor cells at different levels of invasiveness are varied, for example, lower expression of integrins a2b1 (alpha-2-beta-1) and a5b1 (alpha-5-beta1) has been observed in breast cancer [5].

Although research into adhesive proteins (CAMs) sheds new light on the process of cancer cell migration, one should be aware that these discoveries are for now the “tip of the iceberg” in understanding cancer and the mechanism of cancer invasion and metastasis.

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