Integrins in Cancer: From Cell Adhesion to Metastasis

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Introduction

Cancer is a complex and fatal disease involving abnormal growth of cells; it can spread and infiltrate other organs and tissues as well. Of these processes, a central core is formed that is defined by the relationship between the cancer cells and the microenvironment. Integrins are believed to be one of the most important molecules implicated in such interactions. Integrins are a family of transmembrane proteins that enable the cell to adhere to the ECM and transmit signals within the cell that regulate cell survival, differentiation, and motility. Concerning cancer, integrins have been identified in increasing evidence as significant participants in tumor progression and metastasis. In this article, the authors describe the multiple functions of integrins in cancer, starting with the simple concept of cell adhesion and moving up to the triggering of metastasis.

Integrins: Structure and Function

Integrins are extracellular transmembrane proteins with α and β subunits, also known as integrin a and b subunits. The integrin receptors are composed of these subunits in different combinations and each of them has different binding specificities for ligands. For the most part, integrins are transmembrane proteins that act as cell adhesion receptors and bind to ECM molecules like fibronectin, collagen, as well as laminin. Apart from their ability to bind, integrins are also identified as bi-directional signaling platforms. They convey signals from the ECM to the cell, so-called outside-in signaling and vice versa, inside-out signaling, and are involved in the control of many cellular functions, including migration, cell survival, and differentiation.

However, this evidence explains that integrins are involved in normal tissue architecture. Integrins in healthy tissues are involved in the maintenance of the tissues’ cohesiveness as well as their ability to respond to the ECM. However, in cancer cells, these receptors are abnormally expressed, and the cell responses that they meditate on change and actively participate in tumor formation and cancer spread.

Integrins in Tumor progression

In the following sections, it has been described how integrins can promote tumor progression and metastasis. Among the strategies by which they do this is by promoting the survival chances of cancer cells. For instance, integrin α6β4 induces carcinoma cell’s resistance to apoptosis. This integrin plays a role in signaling a cascade that enables cancer cells to live despite their shakiness, for instance, due to hypoxia or lack of nutrients. It is, however, important during the initial stages of tumorigenesis when cells are under stress to survive the hostile tumor environment.

Besides cell survival, integrins also support the process of cancer cells’ division. Integrins binding with ECM proteins, including laminin-5 and fibronectin, can stimulate pathways like MAPK/ERK, which mediate cell cycle advancement and cell division. This is not only observed at the primary tumor site but is highly significant for the metastatic tumor formation at distal sites.

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Integrins and Tumor Invasion

As is one of the characteristic features of most cancers, local infiltration through invasion into surrounding tissues involves integrins significantly. Cell adhesion and movement through Integrin receptors for cell adhesion or ECM components are critical components of cell invasion in or out of tumor mass. Several of the subunits, including α6β4 and αvβ3, have been shown to enhance cell movement and invasiveness since they interact with ECM proteins and also activate intracellular signaling pathways that modulate cytoskeleton movements.

For example, Integrin α6β4 increases the expression of metastasis-promoting factors such as S100A4, which in turn improves the invasive capability of carcinoma cells. This integrin can engage and activate Src kinase; p125FAK is phosphorylated at Y 397, followed by activation of all downstream molecules that result in cell migration and invasive abilities. However, integrin αvβ3 is overexpressed in several human cancers and has been found to mediate the tumor cell invasiveness by stimulating MM’s and consequently causing degradation of the ECM.

This is further amplified by the function of integrins to adjust the tumor microenvironment, making invasion additional efficient. Integrins are also capable of attracting and stimulating different types of stromal cells, such as fibroblasts and immune cells, to the site of the tumor. In response to cancer-associated signals, these stromal cells release molecules that alter the properties of the ECM to promote cancer cell invasion.

Integrins in Metastasis

Invasion is the ability of the cells that constitute the primary tumor to penetrate through the surrounding basement membrane, while intravasation implies entry of the cells into the blood or lymphatics, and the subsequent colonization of new sites through extravasation is called metastasis; this process is the main cause of the deaths due to cancer. Since integrins participate in nearly every step of the metastatic cascade, they have been blamed for cancer detachment, invasive cancer cell proliferation, residence in foreign tissues, and angiogenesis.

In the early steps of metastasis, cancer cells have to break away from the primary tumor mass, which incorporates the down-regulation of cell adhesion molecules and up-regulation of integrins that adhere to the ECM. Integrin αvβ3, for instance, is highly expressed in metastatic cancer cells and allows cell detachment through the activation of MMP that degrades ECM components.

Even as cancer cells get into circulation, integrin is still instrumental in tumor cell survival and migration to distant tissues. Of these, it found that alpha 6 beta 4 enhanced the ability of CTCs to survive and activate signaling cascades that led to cell survival. In addition, other adhesion receptors like integrin αvβ3 and α4β1 help in the attachment of circulating tumor cells to endothelial cells of the blood vessels, which is essential for extravasation and formation of secondary tumor colonies.

Integrins are also involved in the colonization of distant organs through the regulation of the relationship between tumor cells and the surrounding environment. For example, integrin αvβ3 that is presented on the tumor cell membrane can attach to ECM elements in the particular area of bone marrow and contribute to the formation of bone metastases. Second, integrins can mobilize and activate local stroma cells to secure a proper microenvironment for the implantation and growth of metastases.

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Targeting Integrins in Cancer Therapy

Since integrins are involved in cancer progression and metastasis, they have also attracted much attention and developed to be therapeutic targets for cancer. Several therapeutic approaches have therefore been synthesized aiming at antagonizing the function of integrin; these include monoclonal antibodies, small molecule inhibitors, and peptides that prevent integrin ligand interactions.

Cilengitide, an αvβ3, and αvβ5 integrin-binding cyclized peptide mimetic, has been described as a potential anti-cancer agent in previous reports. Cilengitide works by antagonizing specific integrins that promote tumor growth and metastasis; these effects are especially significant in cancers particularly dependent on these particular integrins. Clinical trials have also been done concerning the use of integrin inhibitors as an adjunct to chemotherapy and radiation therapy.

The other method is the application of integrin-blocking antibodies. For example, the antibodies to integrin α6β4 decrease the invasiveness of cancer cells as well as the formation of tumors with metastatic properties. These antibodies target Integrin-mediated signal transduction pathways that are critical for tumor cell survival and motility.

However, there is some controversy about integrin-targeted therapies today: there are still several problems. This means that integrin signaling pathways can be redundant and plastic, and this flexibility is sufficient to create resistance to therapy because the inaccessible expression of further integrins can be activated. Furthermore, integrins are expressed in normal tissues, and this creates the issue of the side effects of integrin inhibitors.

Conclusion

Integrins participate in the progression and metastasis of tumors by focusing on the relationship between tumor cells and their surrounding environment. From cell survival and proliferation to invasion and metastasis, integrins are implicated in every step in the development of cancer. They are involved in the regulation of these processes and, as such, make good targets for therapeutic intervention. So, the research on integrin function in cancer and more advanced and selective therapies aimed at integrin may help to raise the efficiency of cancer treatment.

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