17.8: Mitogens and the Cell Cycle
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase receptors present on the cell membrane, it transmits a growth-inducing signal to the corresponding cells. However, overactivation of EGFR can lead to tumor growth, invasion, and metastasis. It needs to be inactivated in the cancer cells to induce cell cycle arrest, dedifferentiation, or programmed cell death. Hence, the development of novel and targeted cancer therapies requires a deeper understanding of the mechanism and coordination between the mitogen and the cell cycle.
Role of Epidermal Growth Factor (EGF) as a mitogen in cancer therapeutics
In non-malignant tissues, the number of EGFR on the cell surface is tightly regulated to ensure that the cell division rate accurately matches the tissue's requirement. However, in cancerous cells, EGFR is overexpressed and is often perpetually stimulated by EGF or EGF-like proteins secreted by the cancer cell itself. A similar effect may occur when a mutation in EGFR drives the receptor into a state of continual activation. Overexpression of EGFR and closely associated ErbB2 receptors are associated with more aggressive clinical behavior, such as in Grade 3 cancers where tumor cells can likely spread to other parts of the body. Therefore, therapies directed at inhibiting the function of overactive receptors in the cancer cells can be used as anti-cancer therapies.
Monoclonal antibodies (MAbs) that block activation of EGFR and ErbB2 have been developed. These MAbs have shown promising preclinical studies. For example, trastuzumab, an anti-ErbB2 MAb, was recently approved to treat patients with metastatic ErbB2-overexpressing breast cancer. Another MAb, IMC-C225, an anti-EGFR, has shown impressive activity to revert tumor cells' resistance to chemotherapy.