Treatment Therapies

Targeted therapies

Recent developments in Cancer Cell Biology

Cell proliferation is essential to the maintenance of normal, healthy tissue. However, this process must be strictly controlled. There are three major types of control for cell proliferation, although this split is arbitrary as several factors can mediate more than one of these processes:

• Signals from a remote source (e.g. hormones and growth factors)
• Signals from the immediate environment (e.g. growth factors produced by adjacent cells, interactions with the extracellular matrix, etc.)
• Physical interactions with adjacent cells (e.g. contact inhibition).

Tumour development, growth and progression (tumourigenesis) is a multistep process resulting from the loss of the normal constraints on cell growth.

An individual tumour arises from a single cell by clonal expansion. Transformation of a normal cell into a cancer cell requires three to six separate key alterations in the genetic make-up of the cell.¹

Oncogenes

Oncogenes (genes that are capable of causing the transformation of normal cells into cancer cells) were first discovered in ribonucleic acid (RNA)-containing viruses. Infection of isolated cells by such viruses causes uncontrolled cell proliferation and loss of cellular differentiation. These cell behaviours are classic indicators of malignancy.

Importantly, it was soon recognised that each oncogene has a counterpart in the DNA of non-tumour cells (a proto-oncogene) that is essential form normal cellular function. Normal cells can be transformed into tumour cells following alterations in proto-oncogenes that turn them into oncogenes. Several mechanisms are involved:

• Gene rearrangement – relocation of the proto-oncogene within the chromosomes resulting in inappropriate gene expression.
• Deletion or point mutations – the DNA coding sequence for the functional protein is altered.
• Gene amplification – multiple copies of the proto-oncogene are produced.
• Loss of a tumour-suppressor gene resulting in uncontrolled expression of the proto-oncogene.

Most proto-oncogenes (and their oncogenic equivalents) code for proteins involved in the regulation of the normal cell cycle.

Examples of proteins derived from proto-oncogenes include:

• Growth factors
• Growth factor receptors
• TKs (membrane-associated, cytoplasmic)
• Guanine triphosphate (GTP) binding proteins
• Serine/threonine-specific protein kinases
• Gene regulatory proteins.

Growth factors

Many oncogenes code for growth factors. Table 1 summarises examples of growth factors and their functions. Growth factors are abundant in the cellular environment and interact with specific receptors to regulate cell growth and division. Dysregulation of growth factors is one mechanism for uncontrolled cell growth that is a primary characteristic of cancer. Furthermore, transformed cells can over secrete growth factors resulting in positive feedback loops (autocrine stimulation) leading to further tumour growth and development.¹

Table 1. Examples of growth factors and their functions

Growth factor receptors

Other oncogene products include growth factor receptors. Some of these proteins are located in the cell membrane and bind growth factors with a high affinity. Growth factor receptors are very complex. There are several large heterogeneous families with variant forms and differential expression depending on the cell type and its state of differentiation. In general, cell-surface peptide growth factor receptors consist of several domains: an extracellular, ligand-binding domain, a transmembrane region and a cytoplasmic domain.

Intracellular signalling

Growth factors bind to growth factor receptors and alter cellular function via a complex series of downstream signalling. A key step in this process is the activation of TK-activity (located in the cytoplasmic domain of the receptor) by autophosphorylation. Intracellular proteins are then able to bind to the activated TK resulting in phosphorylation of the bound signal protein. There are numerous intracellular signalling proteins, many of which were first discovered as products of oncogenes. Examples of intracellular proteins binding to activated TK domains include phosphatidylinositol 3'-kinase (PI3 kinase), GTPase activating proteins (GAPs), and phospholipase C (PLC) family members. Such molecules then rapidly stimulate intracellular signalling pathways or activate other effector molecules (e.g. proteins and enzymes associated with DNA).

The activation of these pathways ultimately leads to changes in gene expression and therefore induces a variety of cellular responses including proliferation, differentiation and motility.

References:
1. Alberts B, Bray D, Lewis J, et al. Molecular biology of the cell, 3rd ed. Garland Publishing, Inc: New York, 1994.

Treatment Therapies

• Overview
• Chemotherapy
• Targeted therapies
  • Cancer Cell Biology
  • EGFR
  • Rationale for HER1/EGFR
• Current Therapy - Erlotinib
• Monoclonal Antibody Therapy