About the Core Invasive Machinery
On the basis of the data presented in the literature and on the previous
work of the participants to this project, the MetaFight Consortium identifies
the Core Invasive machinery at the adhesive sites as
a major player in regulating cell adhesion, migration and invasion in
the early onset of tumour metastasis as well as in homing of metastatic
cells to target organs.
The state-of-the-art denotes some major and well characterised components of the Core Invasive platform such as integrins, FAK and their proximal effectors as regulators of cancer progression and metastasis outgrowth in multiple ways. As integrins do not possess intrinsic catalytic activity, the signals initiated by ECM-integrin interactions are transduced into cells through the activation of integrin-associated proteins. This can occur through co-clustering with non-receptor PTKs with emphasis on the FAK and Src-family PTKs (SFKs).
Recent studies have demonstrated that the integrin-FAK complex is activated in many tumour cells where the active platform functions to promote cell motility, cell cycle progression and cell survival. As an additional mechanism, integrins can co-cluster with membrane receptor protein-tyrosine kinases such as EGFR, Her2, MET, Ron, all known as dominant oncogenes in transformed cells and with chemokine receptors such as CXCR4, involved in chemotactic response of tumour cells. The complex cross-talk and interplay between all these molecules generates largely undiscovered signals leading to tumour growth and metastasis.
Integrins are heterodimers of alpha and beta subunits that bind the extracellular matrix through their extracellular domains. Modulation of cell-matrix adhesion activates a signalling cascade which drives local motility by reorganizing cytoskeleton and invasion through the activation of matrix metalloproteinases. Their cytoplasmic domains are embedded into a large macromolecular complex consisting of a range of proteins which connect integrins to the actin cytoskeleton.
By promoting invasion and metastasis, integrins have been shown to substantially influence the prognosis of epithelial tumours. Interestingly mutation in the beta 1 integrin subunit has been found in human squamous cell carcinoma exerted constitutive activation of integrin ligand binding, promoted cell spreading and led to sustained activation of downstream signalling (Evans et al., 2003). These data demonstrated that mutations in integrins might affect tumour differentiation, invasion and progression.
Indeed integrin expression differentially affects tumour invasion and metastasis. For example, reduced integrin levels promote cell detachment from the primary tumour and invasive growth, playing a role in the early events of metastasis formation. On the other hand, up-regulation of integrins might account for an increased adhesion of tumour cells in the process of metastasis. Elegant studies with breast cancer cells have demonstrated that the addition of inhibitory anti-beta1 integrin antibodies leads to the reversion of the malignant phenotype in 3-dimensional cell culture and to a reduction in tumour formation in vivo.
Moreover integrins and adhesion of cells to ECM confer higher resistance to ionizing radiation and cytotoxic drugs. Recent data demonstrate that the beta1 integrin transduces pro-survival signals. Cell-ECM interactions prolong the radiation-induced G1 or G2 cell cycle blocks. This is thought to enable the cell to optimize DNA repair and seems at least partly to be responsible for resistance. Induction of apoptosis by cytotoxic agents is prevented by integrin-mediated adhesion to ECM on the basis of up-regulation of the prosurvival proteins in parallel to down-regulation of pro-apoptotic proteins.