Integrins and cancer

An extensive variety of integrins contribute to tumour progression, but because of integrin regulation, ECM composition, concomitant signalling from growth factor receptors, and pleiotropic functions together with their contribution to cancer may differ across different cancer types, stages and treatment, it is significantly complicated to associate a specific cancer-related phenotype to a given integrin. Despite the above, some crucial factors influencing cancer progression has been recognized in particular metastasis.

Each cell type displays a specific range of integrins and this range changes according to the cellular or environmental input. In cancer, changes in the components of the ECM, in

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response to growth factors or due to intracellular alterations such as activation of oncogenes, impact in this integrin’s variety (Table Intro. 2). Moreover, several studies have suggested that integrins on tumour cells are not only altered quantitatively but qualitatively, by changes at phosphorylation and/or glycosylation level, what disturbs the properties of the cytoskeletal and extracellular ligand-binding capabilities. The contribution of these alterations may influence both transformation and tumour progression.

Table Intro. 2 Integrin expression in metastatic tumour cells compared to primary tumour cells.

Cancer Type α1β1 α2β1 α3β1 α6β1 α5β1 αVβ3 α4β1

Adapted table from Antti Arjonen. (2013). Integrins on the move (Doctoral Thesis). University of Turku. Turku, Finland¹⁶¹.

An additional level of regulation is related to the ratio of the receptors between the cell surface and endosomal pools. Cancer cells frequently present altered integrin endocytosis and recycling back to the plasma membrane. Recent studies have shed new light on the controversial ligation-dependent effects. There are evidence about how un-ligated integrins can positively or negatively influence tumour cell survival, thereby affecting tumour growth and metastasis¹⁶². The establishment of more defined mechanisms by which integrins affect tumour cell survival both in the ligated and un-ligated states could be a crucial determinant of the efficacy of integrin antagonists in cancer.

Integrins role in cancer does not finish in tumour cells themselves; they are also relevant on the surface of tumour-associated host cells. The tumour microenvironment is full of several host cell types, including endothelial cells, perivascular cells, fibroblasts, and inflammatory cells, contributing to tumour progression by modulating angiogenesis, lymphangiogenesis, desmoplasia, and inflammation. In line with this, and probably contributing to communication among all of these cell types, it has been demonstrated the role of integrins in cell-to-cell communication, not only acting as a co-receptor for growth factors or oncogenes but also as an important player for EVs biology. Specifically, integrins present in EVs have a functional role in priming the metastatic niche^109,110. EVs released by cancer cells may support metastasis by contributing to the development of organ-specific

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(pre)-metastatic niches through their capacity to transfer metabolites, proteins, and RNA to distant tissues. Extraordinarily, enrichment of integrins on the surface of cancer-derived EVs contributes to organ-specific targeting¹⁶³. For example, α6β1 and α6β4 present in EVs surface secreted by cancer cells, have the ability to promote the cell tumour homing in the lung, while αVβ5 integrin-EVs, home preferentially to the liver108,110,163. Once there, EVs contribute to the creation of a pre-metastatic niche by inducing the expression of specific ECM proteins and pro-inflammatory factors, which allow the recruitment of inflammatory cells.

In summary, integrins show an extraordinary biological role in the link of cells to counter-receptors on other cells and ligands in the ECM, what leads to changes in tumour cell behaviour and microenvironment status by the triggering of a variety of signal transduction pathways¹⁶⁴. Integrin activation can also regulate ECM assembly and the polarity of migrating cells, in that way interceding tumour metastasis and non-tumour cell infiltration¹⁶⁵. In consequence, microenvironmental influences on cell behaviour might be determined by the pattern of integrin expression on the cell surface⁸⁰. Thus, integrins could be interpreted as the hub family of proteins that connects tumour cells and their surrounding microenvironment¹⁶⁴.

Figure Intro. 14. Integrin-dependent functions relevant to cancer.

(Adapted from Begoña Alday-Parejo et al., 2019¹⁶³)

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A great variety of integrins contribute to tumour progression. In one hand, those integrins usually expressed by epithelial cells, the main source of many solid tumours, which includes α6β4, α6β1, αvβ5, α2β1 and α3β1; on the other hand, those integrins typically expressed at low or undetectable levels in most adult epithelia but that have been observed to be highly altered in some tumours, including αvβ3, α5β1, and αvβ6¹⁶². There is an abundant collection of literature supporting these integrin expression pattern alterations in a wide range of cancer types (Table Intro. 3).

Table Intro. 3. Integrins in cancer progression.

Tumour type Integrins expressed Associated phenotypes

Melanoma αvβ3 and α5β1 Vertical growth phase and lymph node metastasis

Breast α6β4, αvβ3, αvβ5 and αvβ6

Increased tumour size and grade, and decreased survival (α6β4). Increased bone metastasis (αvβ3) and increased invasiveness of breast cancer cells (αvβ5). Associated with very poor survival and increased metastases to distant sites (αvβ6) Prostate αvβ3 and αvβ5 Increased bone metastasis (αvβ3) and correlated

significantly with the Gleason pattern (αvβ5) Pancreatic αvβ3 Lymph node metastasis

Ovarian α4β1 and αvβ3 Increased peritoneal metastasis (α4β1) and tumour proliferation (αvβ3)

Cervical αvβ3 and αvβ6 Decreased patient survival

Glioblastoma αvβ3 and αvβ5 Expressed at the tumour-normal tissue margin.

Possible role in invasion. Associated with a poor prognosis/decreased survival

Non-small-cell

lung carcinoma α5β1 Decreased survival in patients with lymph node-negative tumours

HNSCC αvβ5 Lymphatic metastasis and angiogenesis Colon αvβ6 and αvβ3

Reduced patient survival. Significantly associated with T stage and TNM stage (αvβ6) and correlated with poor differentiation and lymph node invasion (αvβ3)

Adapted table from Jay S. Desgrosellier et al., 2010¹⁶⁶ and H.T.A and Ahmedah (2015). Correlation between the expression of integrins and their role in cancer progression (Doctoral Thesis).

Bradford, West Yorkshire, England. University of Bradford, England¹⁶⁷.