The phenomenon of cancer can be defined on various levels. On the most basic level, cancer represents the collapse of the cooperation between the ten million cells of human being . This results in the selfish, uncontrolled growth of cells within the body which eventually leads to the death of the organism.
Cancer as described by the ancient Egyptians (3000 BC to 1500 BC):-
The oldest known description of human cancer is found in an Egyptian seven papyri or writing written between 3000-1500 BC . Two of them, known as the "Edwin Smith" and "George Ebers" papyri .
The Edwin Smith Papyrus describes eight cases of tumors or ulcers of the breast.
Rudolf Virchow , who is often called the founder of cellular pathology , provided the scientific basis for the modern pathologic study of cancer and correlated the clinical course of illness with microscopic findings .
This approach led to the development of modern cancer surgery
2- Families in which cancer is transmitted as a genetic trait e.g. Li-Fraumeni Syndrome , inherited as autosomal dominant trait .
3- Overlap between carcinogens & mutagens .
4- Individuals with DNA repair deficiency syndrome are at increased risk of cancer e.g Xeroderma pigmentosum , inability to repair DNA damage done by U.V exposure leads to high incidence of cancer skin .
Proto-oncogenes are the genes that normally control how a cell divides and the degree to which it differentiates
When a proto-oncogene mutates into an oncogene , it becomes permanently " turned on " or activated
When this occurs, the cell divides too quickly, which can lead to cancer
think of a cell as a car :- A proto-oncogene normally functions in a way that is similar to a gas pedal An oncogene could be compared to a gas pedal that is stuck down, -> cell to divide out of control
These are the intermediate pathways between the growth factor receptor and the cell nucleus where the signal is received.
Like growth factor receptors, these can be turned on or off. When they are abnormal in cancer cells, they are turned on
Two well-known signal transducers are abl and ras . Abl is activated in chronic myelocytic leukemia and is the target of the most successful drug for this disease, imatinib or Gleevec . Abnormalities of ras are found in many cancers.
An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation ( turning on ) of proto-oncogenes , but tumor suppressor genes cause cancer when they are inactivated ( turned off ).
Another major difference is that while the overwhelming majority of oncogenes develop from mutations in normal genes (proto-oncogenes) during the life of the individual ( acquired mutations ), abnormalities of tumor suppressor genes can be inherited as well as acquired .
when a cell prepares to divide into 2 new cells, it must duplicate its DNA. copying errors sometimes occur but cells have DNA repair genes , which make proteins that proofread DNA
The genes responsible for HNPCC (hereditary nonpolyposis colon cancer) are examples of DNA repair gene defects. When these genes do not repair the errors in DNA, HNPCC can result. HNPCC accounts for up to 5% of all colon cancers and some endometrial cancers.
Inherited Abnormalities of Tumor Suppressor Genes
In addition to mutations in p53, RB1 , and the genes involved in HNPCC, several other mutations in tumor suppressor genes can be inherited.
A defective APC gene causes familial polyposis , a condition in which people develop hundreds or thousands of colon polyps
Abnormalities of the BRCA genes account for 5% to 10% of breast cancers .
Non-inherited mutations of tumor suppressor genes
Mutations of tumor suppressor genes have been found in many cancers.
abnormalities of the p53 gene have been found in over 50% of human cancers.
Acquired mutations of the p53 gene appear to be involved in a wide range of cancers, including lung, colorectal, and breast cancer
acquired changes in many other tumor suppressor genes also contribute to the development of sporadic (not inherited) cancers.
Certain types of kidney cancers VHL Kidney cancer Small numbers of colon cancers, melanomas, neuroblastoma NF1, NF2 Nerve tumors, including brain Wilms tumors WTI Wilms Tumor Only rare ovarian cancers BRCA1, BRCA2 Breast and/or ovarian Colorectal, gastric, endometrial cancers MLH1, MSH2, or MSH6 Colorectal cancer (without polyposis) Most colorectal cancers APC Colorectal cancer (due to familial polyposis) Many different cancers INK4a Melanoma Many different cancers P53 Li-Fraumeni Syndrome (sarcomas, brain tumors, leukemia) Many different cancers RBI Retinoblastoma Other non-inherited cancers seen with this gene Abnormal gene Inherited cancer
How Can Oncogenes and Tumor Suppressor Genes Be Used to Help Prevent Cancer?
Several mutations in oncogenes and tumor suppressor genes useful in helping decide which people are at higher risk for developing cancers .
Genetic testing can be used to look for such mutations.
The testing is often expensive
Finding a genetic mutation can have a significant impact on a person’s life , as well as the lives of other family members .
How Can Oncogenes and Tumor Suppressor Genes Be Used to Help Guide Treatment of Cancer?
specific gene changes help predict either patients have a better or worse prognosis or which patients are likely to benefit from certain treatments.
women with breast cancer that contains the HER2/neu (erbB-2) mutation tend to fare worse than women without the mutation .
Some tests for certain gene mutations are very sensitive in finding cancer that persists or returns after treatment. This type of test identify patients at risk of relapse , who might benefit from additional chemotherapy .
Colorectal cancers APC Colorectal cancers MLH1, MSH2 Brain tumors, skin cancers, lung cancer, head and neck cancers, others p53 Burkitt lymphoma, others C-myc Ewing tumor EWS Neuroblastoma N-myc Breast cancer, ovarian cancer, others HER2/neu (erbB-2) B-cell lymphoma bcl-2 Chronic myelogenous leukemia bcr-abl Breast and ovarian cancer BRCA1, BRCA2 Related Cancers Oncogene/Tumor Suppressor Gene
How Can Oncogenes and Tumor Suppressor Genes Be Used to Treat Cancer?
Herceptin may lead to cardiomyopathy or congestive heart failure sprcially if taken with carboplatin , it is recommended that Herceptin is not given to people with a history of heart disease or high blood pressure.
2- Flu-like symptoms
This includes a high temperature ( fever ) and chills, shortly after the drug is given.
Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), and PDGF-R (platelet-derived growth factor receptor).
In chronic myelogenous leukemia , the philadelphia chromosome leads to a fusion protein of abl with bcr ( breakpoint cluster region ), termed bcr-abl . As this is now a continuously active tyrosine kinasae, imatinib is used to decrease bcr-abl activity.
The hope is that a generalized antitumour immune response will be elicited.
In theory, the cytokines could be administered systemically , removing the need for viral modification. However, the level of systemic cytokine required to induce an antitumour response inevitably produces systemic toxicity .
The ex vivo approach permit the local production of high concentration cytokine within the microenvironment of the tumor, without significant systemic level being produced .
The main function of GM-CSF is to cause maturation of Antigen-presenting cells (APCs).
APCs detect antigens released by tumor cells processing them & presenting them in association with class I & class II MHC to T-cells in local lymph nodes there by eliminating the need for the tumor to present antigens directly by itself .