1.7 Oncogene Activation in Cancer Cells Foundations

Oncogene Activation in Cancer Cells Foundations is the body of foundational concepts describing how normal cellular genes that promote cell growth, division, or survival become converted into abnormally active drivers of malignant behavior, and how the resulting activated genes exert their effects on cancer cell physiology. These foundations establish the identity of the normal genes subject to this conversion, the mechanisms by which their activity becomes abnormally elevated or unrestrained, and the consequences that this abnormal activation produces for the growth and survival of the affected cell.

The Concept of the Proto-Oncogene

Normal Genes With Growth-Promoting Function

Within the normal genome, a defined set of genes encode proteins that participate in promoting cell growth, cell division, or cell survival, functioning as components of the ordinary signaling pathways that a cell uses to respond appropriately to external growth signals. In their normal, unaltered form, these genes are referred to as proto-oncogenes, reflecting their potential to become cancer-promoting genes under certain conditions rather than any inherent abnormality in their unaltered state.

Conversion Into an Oncogene

A proto-oncogene becomes an oncogene when it acquires an alteration that increases its activity, removes its normal regulatory constraints, or otherwise causes it to promote cell growth in an inappropriate or excessive manner. This conversion transforms a gene that previously operated under normal regulatory control into one that drives abnormal cellular behavior independent of that control.

Mechanisms of Oncogene Activation

Activation Through Point Mutation

A proto-oncogene can be converted into an oncogene through a mutation affecting a small number of nucleotides within its coding sequence, producing an altered protein product that remains constitutively active or that has lost its dependence on the upstream signal that would normally regulate it.

Activation Through Gene Amplification

A proto-oncogene can be converted into an oncogene-like driver through amplification, in which additional copies of the gene are generated within the cancer cell's genome, resulting in an increased overall quantity of the gene's normal protein product and a correspondingly increased level of the growth-promoting signaling that protein contributes.

Activation Through Chromosomal Rearrangement

A proto-oncogene can become abnormally activated through a chromosomal rearrangement that places it under the control of a different gene's regulatory elements, or that fuses its coding sequence with that of another gene, producing either abnormal overexpression of the unaltered protein or an entirely novel, abnormally active fusion protein.

Activation Through Epigenetic Alteration

A proto-oncogene can also become abnormally activated through epigenetic mechanisms, such as loss of repressive chromatin marks or removal of silencing methylation at its regulatory region, resulting in inappropriate expression of the gene without any accompanying change to its underlying sequence.

Functional Consequences of Oncogene Activation

Dominant Behavior at the Cellular Level

Because oncogene activation typically produces a single altered allele capable of driving abnormal growth signaling, its effect is dominant at the cellular level, meaning that a cell carrying one activated oncogenic allele alongside one normal allele can nonetheless display the abnormal growth-promoting behavior conferred by the activated allele.

Persistent or Amplified Growth Signaling

The unifying functional consequence of oncogene activation, regardless of the specific mechanism involved, is the generation of a growth-promoting signal that is stronger, more persistent, or less dependent on normal regulatory input than the signal generated by the corresponding proto-oncogene in its unaltered state.

Significance of Oncogene Activation Foundations Within Cancer Cell Biology

A Core Category of Driver Alteration

Oncogene activation stands alongside the loss of function of growth-restraining genes as one of the two principal categories of driver alteration recognized in cancer cell biology, and the presence of an activated oncogene within a cell's genome is frequently associated with a significant contribution to that cell's abnormal proliferative behavior.

A Basis for Targeted Therapeutic Approaches

Because an activated oncogene frequently produces a specific, identifiable abnormal protein or an abnormally elevated level of an otherwise normal protein, the foundational understanding of oncogene activation provides the conceptual basis for approaches that specifically target the abnormal product or activity generated by the activated gene.