WEEK 3: Natural History of cancer Flashcards
What is meant by natural history of cancer?
The natural history of cancer is the process of development and progression of cancer from its origin to its final outcome, when uninterrupted by treatment.
State the 4 main determinants of natural history of cancer.
Biological
Evolutionary
Social
Behavioral
Describe the biological determinants of natural history of cancer.
- Normal cell division (growth and replacement)
Cell characteristics
*Mitosis (cell division)
*Differentiation
-Embryo cells are totipotent, with potential to divide and give rise to the adult cells in the body whereas
-Most adult cells are differentiated-have become specialized in structure and function e.g., muscle cells are elongated with contractile proteins.
- CELL DIFFERENTIATION
*In the adult, the replacement of shed or worn-out cells takes place by division of somatic stem cells (also called adult stem cells), which are not fully differentiated, these give rise to only a limited number of cells.
*Hemopoietic stems cells (bone marrow), divide to produce progenitor cells which give rise to blood and immune cells (red blood cells, lymphocytes, neutrophils, eosinophils, basophils, monocytes, and platelets).
*Bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells) can generate bone, cartilage, and fat cells.
Describe how cell differentiation is regulated.
Cell differentiation involves the activation or inactivation of certain genes in response to the cell’s interactions with its neighboring cells and with its extracellular matrix (ECM).
Receptors on the cell will bind to specific molecular elements in the ECM, and this binding activates intracellular signal transduction pathways that turn certain genes on or off.
As a result of these interactions, some genes can be expressed in a given cell, but others cannot.
For example:
*In a muscle cell, the genes that encode the contractile proteins actin and myosin are activated while that encoding for insulin synthesis is inactivated.
Molecular basis of cancer involves the cell cycle.
Describe the G0 phase of the cell cycle.
Many cells in the adult are not actively in the process of replicating; this is shown in the diagram as “cells that cease division,” also known as the G0 phase or the “resting phase.”
The term “resting phase” is a misnomer since the cell is actively carrying out its normal specialized function and is only resting in the sense that it is not actively dividing.
Describe the normal events of a cell cycle.
When additional cells are needed, the cell will receive signals that promote cell division -Cyclin dependent kinases (CDK).
These signals will push the cell to complete the G1 phase (cell enlargement), the cell is metabolically active and continuously grows and proceed to the S-phase, during which DNA is replicated.
In the G2 phase the cell prepares for division by increasing in size and replicating intracellular organelles.
It then divides through mitosis (the M-phase).
Describe what happens at the G1 to S-phase transition of the cell cycle.
The critical phase is the transition from G1 to S-phase. It is carefully regulated by multiple factors, some of which promote the transition.
Genes known as proto-oncogenes can be switched on to produce proteins which facilitate the transition to the S-phase.
Counteracting this push to reproduce are genes known as anti-oncogenes (also called tumor suppressor genes) that inhibit transition to the S-phase.
What is apoptosis?
It is estimated that over _________cells undergo apoptosis daily in adults.
- Apoptosis or programmed cell death is an essential process for removing cells that are stressed, damaged, or worn out.
It is estimated that over 50 billion cells undergo apoptosis daily in adults.
- Apoptosis is also carefully regulated through complex mechanisms. Mutations that affect these regulatory pathways have the potential to contribute to carcinogenesis by failing to eliminate abnormal neoplastic cells or by failing to eliminate cells with other mutations that are premalignant.
*Defects in apoptosis can also cause resistance to chemotherapy, radiation, and immune-mediated cell destruction.
Describe the contribution of Protooncogenes, Oncogenes and Oncoproteins in cancer development.
*Oncogenes are genes that promote autonomous cell growth and protooncogenes are their normal cellular counterparts.
*Various types have been described e.g., viral oncogene, v-onc
The mutant form of RAS protooncogene was one of the first oncogenic sequences detected in cancer.
Growth factors –cancer cells have the ability to synthesize the same growth factors to which they are responsive.
Most cancer develop by acting on tumor suppressor gene p53.
What is other name for p53 gene?
What chromosome is it located in?
State the 2 main function of p53.
p53 is the guardian of the genome.
It is located on chromosome 17p13.1 and is the most common target for genetic alteration in human tumors.
More than 50% of human tumors possess mutations in this gene.
*Its function is cell-cycle arrest
*Apoptosis in response to DNA damage.
What is tumor immune escape?
Is a phenomenon by which tumor cells can grow and metastasize by avoiding recognition and attack by the immune system through various mechanisms, which is an important strategy for tumor survival and development.
e.g., via PD-1/PD-L1, CTLA4/B7, IDO and other pathways leading to treatment failure.
State 7 major essential alterations for malignant transformation.
1.Self-sufficiency in growth signals:
When oncogenes are activated, tumors can proliferate without external stimuli.
- Insensitivity to growth inhibitory signals:
Tumor cells may not respond to signals that are inhibitory to the proliferation of normal cells such as transforming growth factor- β(TGF-β) & direct inhibitors of cyclin dependent kinases.
- Limitless Replicative potential
Tumor cells have unrestricted proliferative capacity associated with maintenance of telomere length and function.
After each cell division there is shortening of certain structures called telomeres found at the end of chromosomes.
Once shortened beyond a certain point there is activation of p53-dependant cell cycle checkpoints as a result of loss of telomere function.
Once activated, apoptosis will ensure, however tumors evade apoptosis with mutations in the TP 53 gene.
- Evasion of Apoptosis: tumors may resist programmed cell death
Just as cell growth is regulated by growth-promoting and growth-inhibiting genes, cell survival is conditioned by genes that promote and inhibit apoptosis.
Therefore, the accumulation of neoplastic cells may occur not only by activation of oncogenes and inactivation of tumor suppressor genes but also by mutations in the genes that regulate apoptosis.
BCL-2 is a gene that protects cells from apoptosis when overexpressed. e.g., lymphomas.
5.Defects in DNA repair
A disability in the DNA repair genes can lead to widespread mutations in the genome and neoplastic transformation.
Failure to repair DNA damage caused by carcinogens or unregulated cellular proliferation will promotes tumor development.
Hereditary Nonpolyposis Cancer Syndrome (HNPCC) has defects in DNA mismatch repair genes hence persons with this condition are predisposed to colon cancer.
Xeroderma pigmentosa also arises from defects in DNA repair genes.
BRCA-1 & BRCA-2: Two genes associated with occurrence of breast cancer. These defects are transmissible.
- Sustained angiogenesis
Tumors stimulate growth of host blood vessels a process called angiogenesis which is essential in supplying nutrients to the tumor.
Tumors are unable to grow without formation of a blood supply which is induced by various factors e.g., most important is vascular endothelial growth factor (VEGF).
Neovascularization has a dual effect on tumor growth.
Angiogenesis supports continued tumor growth and metastasis.
7.Ability to invade and metastasize
*Invasion and metastasis are important biological characteristics of malignant tumors.
*Metastasis is the cause of most cancer deaths and depends on processes that are intrinsic to the cell or those initiated by signals from the tissue environment.
Cancer is preventable. Describe how cervical cancer can be prevented.
Vaccination against the human papilloma virus (HPV) and screening for pre-cancer or cancer are key tools to prevent the 530 000 new cervical cancer cases diagnosed annually.
Despite revolutionary advances in technology, cancer has continued to baffle scientists.
Outline some of the evolutionary attempts to prevent cancer.
Preventative vaccines
High resolution imaging diagnostics
Genome-guided personalized medicines as well as
Drugs that provide cure of potentially lethal cancers
What is intra-clonal diversity?
- Intra clonal diversity
*Provides the greatest challenge to therapeutic control of cancer due to dynamic genetic diversity coupled with epigenetic plasticity, within each individual cancer.
- Advances in cancer genomics using gene sequencing techniques have shown presence of intra-clonal genetic diversities.
*This is now thought to be the reason for resistance and recurrence of cancer even with the best targeted therapy.
