Saturday, July 24, 2010

Introduction To Cancer Biology

There has been tremendous advances in cancer biology and cancer medicine from the time I studied basic medical sciences.

In my preparation for the next Problem Based Learning for the medical students on neoplasm, I found that there are so many new advances that do sound alien to an emergency physician. As mentioned by Harold Varmus, MD, in his lecture on Why Cancer Biology and Cancer Medicine is Finally Emerging (YouTube video attached below), in the era of the 1970s - 1990s, the sphere of cancer biology and cancer medicine are actually two different worlds with little interaction between them, but as from 1990s onwards, these two spheres are beginning to overlap more and more and in fact, is starting to emerge as one due to the fact that more and more specific target therapies have been developed and already used in clinical setting; one of the most popular example is the poster-child drug in CML, imatinib (brand name, Gleevec)

Basically a neoplasm is defined in many text as “… is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues, and persists in the same excessive manner after cessation of the stimuli which evoked the change”. (This would differentiate a dysplasia, where the process is usually reversible when the stimuli is removed).

From my understanding, basically cell growth is regulated by the balance between the activities of proto-oncogene and the tumor suppressor gene. A proto-oncogene promotes cell growth and gene transcription whereas a tumor suppressor gene (the famous one, being p53) acts as a "genomic guardian" that plays an important role in maintaining the DNA integrity. It does so by sensing genomic changes, thereby halting the cell cycle and initiating DNA repair. If the DNA is beyond repair, apoptosis cell death will be initiated. Unfortunately, the proto-oncogene can undergo point mutation, resulting in an oncogene, and thus causing uncontrolled, invasive cell growth. On another hand, the tumor suppressor gene can undergo mutation as well resulting in cancer. Mutation in p53 gene for example, has been cited to cause more than 50% of cancer.

Take a look at the video below and see the role of proto-oncogene and tumor suppressor gene.

But how does a proto-oncogene becomes an oncogene? See the video below.

The 6 Hallmarks of cancer cell:
  1. Self-sufficiency in growth signals
  2. Sustained angiogenesis
  3. Insensitivity to anti-growth signals
  4. Evasion of apoptosis
  5. Limitless replicative potential
  6. Tissue invasion and metastatsis capability
The Mechanism of Action of Imatinib (Gleevac)

Normally, tyrosine kinase proteins respond to external cellular messaging proteins which then translate into a series of reactions that culminate in cellular replication.

Conversely, mutated chromosome, for example, the Philadephia chromosome due to reciprocal translocation of chromosomes 9 and 22 results in the BCR-ABL genetic domain within chromosome 22.

This encodes for a mutant form tyrosine kinase. Unfortunately, this BCR-ABL is constitutively active and does not require activation by cellular messaging proteins in order to stimulate cellular replication. This results in acceleration of cell division, an inhibition of DNA repair, overall genomic instability, and the fatal blast crisis characteristic of CML.

By specifically targeting and competively inhibiting the ATP binding site on BCR-ABL tyrosine kinase, it prevents the phosphorylation the tyrosine residue, and thus, rendering it inactive to further abnormal cellular replication.

Watch the video below:

Apoptosis vs Necrosis

Apoptosis is a form of programmed cell death, and is not due to some external stimuli. It does not have the elements of inflammation. The cellular organells are intact. Rather, it involves chromatin aggregation with nuclear and cytoplasmic condensation. These cellular blebs will then phagocytosed by the macrophages. On the other hand, necrosis is due to an inflammatory reaction to external stimuli including chemical toxins and hypoxia. It results in cellular disintegration with influx of H20 and ions causing cellular swelling.

Though it may seems that cancer biology has nothing much to do with emergency medicine, it is always good to fill in the knowledge gap, and to be constantly upgrading your knowledge. That's one of the reasons why I love to facilitate a PBL discussion. Furthermore, although, oncology is probably the first specialty where the demarcation between clinical medicine and molecular research has been blurred; but who knows, as the impact of molecular medicine is getting more and more important, that it may play an important role in other clinical specialties as well, including emergency medicine!

Finally............a one hour lecture by Nobel Prize winner, Harold Varmus on recent advances on cancer biology (he highlights particularly on myc and K-ras gene):

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