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.

Unicellular organisms, such as bacteria, divide when there are enough nutrients in the environment.

However, in multicellular organisms, most cells remain in G0, or the non-dividing phase, until cell division is triggered by extracellular signal molecules, called 'mitogens’.

Mitogens are usually small proteins or peptides secreted in response to different stimuli, such as tissue injury, infection, or a routine regeneration.

For instance, in the case of tissue injury, specialized cells secrete a mitogen called Platelet-derived growth factor or PDGF.

Such mitogens can bind to the extracellular domain of tyrosine kinase receptors such as PDGF-Receptor, inducing receptor dimerization and autophosphorylation of its intracellular domains. This allows phosphorylation and activation of the downstream intracellular molecules that are involved in multiple signaling pathways.

The mitogen-activated protein kinase or MAP kinase cascades are a type of signaling pathway induced by mitogen-receptor binding. This pathway starts with the activation of the small membrane bound GTPase named Ras by the receptor.

Next, active Ras triggers the MAP kinase cascade which includes a series of kinase proteins. In a chain of phosphorylation reactions, first MAP3 kinase activates MAP2 kinase, and then finally MAP kinase.

Active MAPK then translocates into the nucleus where it activates regulatory transcription factors, including Myc.

Myc increases the expression of G1 cyclins that partner with cyclin-dependent kinases or Cdks.

The G1 cyclin-Cdk complex phosphorylate Rb - a tumor suppressor protein - freeing the bound gene regulatory factor-E2F. Active E2F then binds to a specific DNA sequence and triggers transcription of cell cycle genes that encode several proteins necessary for cell division.

As the mitogenic stimuli recede, such as during the healing of injured tissues, Rb protein interacts with E2F inhibiting its activity, thus, preventing excessive cell growth.