Receptor, Signal, Nucleus, Action: Signals That Pass through Akt on the Road to Head and Neck Cancer Cell Migration

SIMPLE SUMMARY: The ecosystem that surrounds a tumour, the microenvironment, has a huge impact on the spread of cancer, but its exact role in the molecular mechanism of spreading is still under scrutiny. This literature review aims to focus on the evidence published on the production of growth factors or proteins from the tumour microenvironment, which initiate signals in cancer cells. This review provides evidence that when Akt, a signalling protein, is activated by different growth factors such as epidermal growth factor, transforming growth factor α/β, vascular endothelial growth factor and nerve growth factor, head and neck cancer cell spreading is stimulated. In a nutshell, it demonstrates that the tumour microenvironment plays an important role in cancer spreading by synthesising and secreting growth factors and suggests that targeting growth-factor-activated Akt in combination therapy could be a valuable therapeutic approach in treating head and neck cancer patients. ABSTRACT: This review aims to provide evidence for the role of the tumour microenvironment in cancer progression, including invasion and metastasis. The tumour microenvironment is complex and consists of tumour cells and stromal-derived cells, in addition to a modified extracellular matrix. The cellular components synthesise growth factors such as EGF, TGFα and β, VEGF, and NGF, which have been shown to initiate paracrine signalling in head and neck cancer cells by binding to cell surface receptors. One example is the phosphorylation, and hence activation, of the signalling protein Akt, which can ultimately induce oral cancer cell migration in vitro. Blocking of Akt activation by an inhibitor, MK2206, leads to a significant decrease, in vitro, of cancer-derived cell migration, visualised in both wound healing and scatter assays. Signalling pathways have therefore been popular targets for the design of chemotherapeutic agents, but drug resistance has been observed and is related to direct tumour–tumour cell communication, the tumour–extracellular matrix interface, and tumour–stromal cell interactions. Translation of this knowledge to patient care is reliant upon a comprehensive understanding of the complex relationships present in the tumour microenvironment and could ultimately lead to the design of efficacious treatment regimens such as targeted therapy or novel therapeutic combinations.