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Oncogenes: The Final Common Pathway

Viruses, chemicals and radiation have as their target the proto-oncogenes that regulate normal proliferation and differentiation of cells, as well as genes (loss of suppressor genes) that regulate their action and also genes involved in regulating the cell cycle. Multiple events are involved, at least two, over a long period of time. In the case of hereditary cancers like retinoblastoma, one of these mutational events is inherited increasing the probability that the further event(s) will occur. The damage is multiple involving point mutations, amplification, duplication and translocation of affected genes.

These genes regulate normal growth pathways so that defects may involve growth factors themselves in the extracellular space, growth factor receptors on the cell’s plasma membrane, second messenger systems which convey signals from cell membrane receptors across the cytoplasm to the nucleus (adenylate cyclase, G-proteins, tyrosine protein kinases), and oncogenes like myc, myb and fos which regulate nuclear function. The signals result in cell activation followed by growth and differentiation. The process is diagrammed in the figure below where the abbreviations represent examples of oncogenes.

The final result is malignant transformation and then the development through further genomic instability the properties of invasiveness and metastasis.

Malignant transformation is a complex event that involves extensive intracellular phosphorylation with profound alterations of cellular function and morphology. The following list shows how widespread these changes are.

• Unrestrained growth

* Increased saturation density
* Increased growth factor requirements
* Loss of capacity for growth arrest
* Loss of dependence on anchorage for growth
* Loss of contact inhibition of movement
* Changed growth habits

• Changed cell morphology
  * Anaplasia
  * Loss of actin microfilaments

• Cell surface alterations
  * Easier agglutination by lectins
  * Increased glucose transport
  * Reduced or absent surface fibronectin
  * Protease secretion

• Altered gene transcription
• Release of transforming growth factors
• Immortalization

Metastasis is an equally complex process in which cells can migrate from the primary tumor regionally through lymphatics or by implantation in the pleural or peritoneal space, and systemically through capillaries and small vessels into the bloodstream. Metastasis occurs often in tumor-specific patterns that depend on the anatomy of lymphatic and circulatory drainage arrangements. These assist the clinician in estimating and predicting the degree and location of tumor spread.

The process is described as a metastatic cascade. The initial tumor focus grows large enough to become vascularized through the action of substances like tumor angiogenesis factors. Through local mechanical and enzymatic processes cells become detached from the local tumor mass to invade the surrounding tissues, often disrupting their normal histologic structure. Eventually some of these detached tumor cells invade and pass through the walls of local lymphatics and small blood vessels, eventually arriving into the circulation where the action of clotting factors such as platelets may coat and aggregate them, thus protecting them from host defenses like the immune system as they circulate. Some of these circulating tumor cells arrest at distant sites and adhere to vessel endothelium. They extravasate by migrating between the endothelial cells (diapedesis) and then penetrate the supporting basement membrane of the vessel using enzymes. They set up a local tumor focus and the process begins again. The altered properties of the cell membrane of the tumor cell play an important role in this process.

The genetic instability of the tumor cell which gives rise to its morphological and functional heterogeneity also plays a role. Through a process analogous to Darwinian population genetics it generates variants which through selective processes eventually display the right combination of properties to be able to pass successfully through all of the steps of the metastatic cascade to establish a new tumor focus.

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