Cancer in general:
- Cancer is a disease that affects people of nationalities and age groups.
- All cancers start with mutations in one cell.
- There are many types of cancers that can occur in any organ or tissue of he human body which are:
1) Solid tumors (form lumps)
2) Liquid tumors (flow freely in the blood)
- Less than 10% of all cancer mutations are inherited. Usually it arises as a result of environmental factors.
- DNA mutation can produce mutant protein.
- When accumulation of mutant protein produced it will transforms a normal cell into a cancerous one.
- As we age, we accumulate more and more mutations. This explains why cancer incidence increases with age.
- The mutation can cause disruption of cell's growth life cycle, proliferation and death.
Causes of Cancers:
- Causes of cancers can be divided into 3 types according to epidemiologists as stated below:
1) Inherited factors = less than 10%
2) Synthetic chemicals factors (pollution, food additives, etc) = less than 5%
3) Environmental, dietary, cultural, or lifestyle factors = 85%
- As for oral cancer, although it has multifaceted etiology, tobacco use and alcohol consumption are widely considered to be its major risk factors.
- Tobacco use remains the single most important and preventable cause of this disease.
Killers in smoke
- A cigarette smoker inhales over 60 known/suspected cancer-causing agents (carcinogens), including polyaromatic hydrocarbons (PAHs), nitrosamines, and heavy metals.
- Smoke moves with inhaled air down the respiratory tract – from the trachea to the bronchi, and then branching into ever-smaller bronchioles.
- The bronchioles end in alveoli sacs where nicotine, carbon monoxide, and other gases in cigarette smoke are exchanged with the blood.
- Carcinogens can then enter the cells and cause DNA damage.
- The damaged cells may eventually progress to oral cancer.
- K-ras and p53 are the two genes most frequently mutated in smoking-related cancers.
- One tar component, benzo[a]pyrene, is specifically linked to known mutations in these genes – providing the equivalent of a "smoking gun" at a murder scene.
K-ras
- The protein produced by the K-ras gene is a tumor “activator.”
- Its overactivity contributes to tumor development.
- The K-ras protein resides on the inner side of the cell membrane, where it conducts growth signals from cell-surface receptors to the nucleus.
- This process is called signal transduction.
- Signal transduction begins with the arrival of a growth factor at the cell surface, where it recognizes a specific receptor anchored in the cell membrane. The binding of the growth factor to its receptor conducts a growth signal into the cell interior.
- The K-ras protein accepts the growth signal and, in turn, relays it to other molecules in the cytoplasm. Raf and other signal transducers are protein kinases, which activate other molecules by adding phosphate groups.
- This signaling cascade culminates in the nucleus with the activation of Fos and Jun, two transcription factors that join together to initiate transcription of genes involved in cell replication.
- Mutations in the K-ras gene result in a K-ras protein that is essentially stuck in an “on” position – perpetuating a signaling cascade in the absence of any real signal from a growth factor.
P53
- The p53 protein is a tumor suppressor, its activity helps counter tumor development.
- P53 occupies a “checkpoint” in the cycle of cell division, where it “senses” DNA damage or mutations.
- The cell cycle is composed of four stages:
- During the first Gap Phase (G1) the cell grows and replenishes its resources.
- During S Phase (S) the cell synthesizes DNA in preparation for cell division.
- During the second Gap Phase (G2) the cell synthesizes proteins and other cellular components needed for cell division.
- During Mitosis Phase (M) the cell divides into two daughter cells.
- P53 acts as a checkpoint into the critical Synthesis (S) and Mitosis (M) Phases. After receiving information from DNA repair systems, p53 can signal the cell to stop dividing, allowing time for a mutation to be repaired before it is passed on to daughter cells.
- For example, p53 arrests the cell cycle, allowing time to repair G-T mutations induced by benzo[a]pyrene.
- If the DNA damage is too great to repair, p53 can signal the cell to commit suicide by the process called apoptosis, or programmed cell death.
- Mutations in p53 cause a loss of checkpoint control, allowing mutations and DNA damage to accumulate in a cell lineage.
- Carcinogen connection : The classic mechanism of carcinogenesis is based on the fact that carcinogens, when they are activated, end up causing DNA adducts and DNA damage.
Diagnosis and Treatment:
Tumor profiling (microarrays)
- Based on set of genes one can see big differences between the molecular pattern of these tumors and as these investigators noted, this correlates with the probability with which the disease will progress, within five years of being diagnosed.
- Why is this important? Clearly it shows that despite the fact that these patients have similar pathologies they're molecularly very different.
- This information in the future could allow oncologists to decide whether or not additional therapy, for example chemotherapy, would be required.
- In the case of those patients that had the good prognostic gene expression pattern, would perhaps not require chemotherapy in addition to surgery and therefore they would be spared the devastating side effects of that therapy.
- By understanding the natures of some of the genes that go up in these poor prognosis tumors it might be ultimately possible to design drugs that would specifically target these genes and then treat those cancers in a much more rational way.
