Cancer Biology Overview

• Cancer is a group of over 100 diseases affecting a wide range of tissues in the body.
• Mutations in genes controlling cell growth, often after exposure to carcinogens causes cancer.
• Most mutations occur in somatic cells, but some cancers cluster in families, sharing environment and genes.
• Around 1% of mutations are inherited, but additional somatic mutations are generally required for cancer development.
• Cancer is characterised by a loss of growth control, leading to an unregulated increase in cell number.
• Metastasis and invasion of other tissues also characterizes cancer.
• Cancers differ based on tissue of origin, causal factors, and molecular mechanisms.
• Cancer affects 1 in 3 people.
• Cancer is the leading cause of death in New Zealand and second worldwide.
• In New Zealand in 2015, there were 23,215 new cases of cancer and 9,615 deaths.
• Roughly half of the people who get cancer will die from it.
• Tumor growth can be very rapid.
• Tumor is classified according to tissue of origin.

Benign Tumors

• Cells are well-differentiated.
• Cells look much like normal cells.
• They may perform the normal function of the tissue.
• Cells grow relatively slowly.
• Their growth is suppressed by apoptosis and contact inhibition.
• Size may be limited to just a few mm due to lack of blood supply.
• Surrounded by a fibrous capsule and confined to the original location.
• Do not infiltrate, invade, or metastasize.
• Benign Tumors can damage nearby organs by compressing them.

Malignant Tumors

• Cells are less differentiated.
• Cells do not look like normal cells.
• Do not perform the normal function of the tissue.
• Cells secrete new signalling molecules, enzymes, or toxins.
• Cells grow rapidly since they have lost the ability to control proliferation and differentiation.
• No fibrous capsule.
• Cells infiltrate and invade surrounding tissues.
• Cells metastasize to form new tumors at distant sites

Tumour Classification

• Classify according to tissue of origin
• Benign tumours have a tissue name + "-oma"
• "Carcinomas" are derived from epithelial cells
• "Adenocarcinomas" are derived from glandular epithelial cells
• "Sarcomas" are derived from mesenchymal cells
• "Leukaemias" are derived from haemopoietic cells

Regulation of Cell Number

• Most cells in adult tissues are terminally differentiated and quiescent (non-dividing).
• Exceptions include hair follicles, blood, and gut stem cells.
• Within each tissue, cell death, by apoptosis or necrosis, is balanced by cell division, often of stem cells, leaving the total number of cells constant.
• Cell division is tightly regulated by growth factors.
• Growth Factors allow quiescent cells to enter the cell cycle and divide.
• If differentiated cells start dividing again or dividing cells lose control of growth then this can lead to cancer.
• Adult cells are terminally differentiated and no longer divide, they are quiescent.
• Transit through the cell cycle is regulated by checkpoints.

Cell Cycle Checkpoints

• Controlled by cyclin-dependent kinases (CDKs) and CDK inhibitors.
• Correct sequence of phases (G1, S, G2, M).
• Cellular and environmental conditions are favorable.
• DNA is properly replicated and undamaged.

G1/S Transition Checkpoint

• Growth Factors must be present.
• Nutrients must be available.
• DNA must not be damaged.
• The cell must be big enough.
• Failure to meet these criteria causes cell-cycle arrest and can lead to cell death by apoptosis.
• The G1/S checkpoint is regulated by growth factors and DNA Damage
• Transit through the G1/S checkpoint require an active Cdk4/6-cyclinD complex
• Cdk4/6 is activated by growth factors
• p21 & p27 are Cdk inhibitors that inhibit Cdk4/6
• "Cells need growth factors and intact DNA to progress through G1/S"

p53

• a transcription factor induced by DNA damage controls expression of p21 and p27
• p53, p21 & p27 are examples of Tumour Suppressors as they inhibit cell division

Types of Mutations

• Cancer is caused by mutations in genes controlling cell number.
• Increase of proliferation through Mutations
• Decrease in cell death(apoptosis) through Mutations
• Mutation of DNA repair genes lead to genome instability.
• This makes further mutations more likely.
• Most mutations are somatic and acquired by environmental interactions, such as exposure to carcinogens and lifestyle factors.
• Some germline mutations may be inherited and predispose someone to cancer E.g. Rb – retinoblastoma, BRCA1/2 – breast cancer
• A single mutation is not enough
• Cancer arise from an accumulation of several mutations over a lifetime which is a "multi-hit hypothesis"
• From 2 to 20 mutations depending on the type of cancer

Recognizing Genetic Factors in Cancers

• Allows for screening individuals who are at particular risk
• Allows inherited mutations
• Can fingerprint the cancer
• Allows Diagnosis and targeted treatments.
• Develop understanding mechanism and development of new therapies
• Many genes mutated in cancer identified
• Fall into two main types, which positively & negatively regulate cell proliferation

Proto-oncogenes/Oncogenes

• Mutated forms of normal genes that positively regulate cell division
• proto-oncogenes encode components of growth factor signalling pathways
• that stimulate cell proliferation by allowing progression from Go/G1 into S-phase when growth factors are present
• Growth factors (EGF) & receptors (HER2)
• Signalling proteins (Ras) & protein kinases (Src, Abl)
• Transcription factors (Myc, Jun, Fos)
• Point mutations, insertions, deletions, translocations
• A gain of function
• Stimulates cell proliferation in the absence of growth factors (e.g. Ras-MAPK pathway > > > G1/S transition)

Tumour Suppressor Genes (TSGs)

• Negatively regulate cell division
• Usually encode proteins at cell cycle checkpoints Mutations can cause a loss of function

Control of Cell Number

• Cancer happens when differentiated cells start dividing again or dividing cells lose control of growth.
• Cell division is tightly regulated by growth factors.

Telomere Length and Cell Lifespan

• Cells contain telomerase, which can elongate telomeres.
• Telomerase activity is essential for allowing cells to keep proliferating.
• Increased telomerase activity allows cells to proliferate indefinitely and leads to cancer.

Metastasis.

• In multiple distant sites and rapid growth is life threatening.
• Altered cells simulated to divide by a tumor promote.
• Altered cell may remain dormant or be remove by immune system.
• The hallmark capability of malignant tumor cells to move to different body sites.

Stages of Cancer Development

• Initiation: Exposure to a chemical, physical, or biological carcinogen causing DNA damage.
• Promotion: Stimuli by tumor promoters promote proliferation of initiated cells.
• Progression: Tumor cells acquire more malignant changes.

Cell properties during Metastasizing

• Loose of adhesion;
• Gain of motility (secretion of proteases)

Factors That Act As Promoters

• Reproductive hormones
• Obesity
• Lifestyle

Host Risk Factors

• Hereditary predisposition
• Reproductive hormones
• Obesity
• Immune surveillance

Environmental Risk Factors

• Chemical carcinogens (mutagens)
• Viruses & bacteria
• Radiation

Chemical Carcinogens

• mutagens that cause DNA damage
• DNA modifying chemicals causing mutations
• Lifestyle - cigarettes, alcohol, diet
• Occupational exposure

Clinical Manifestations of Cancer

• Local effects: physical effects due to compression or blockage of structures. Effusions – build up of fluid.
• Systemic effects: malnutrition, fluid and electrolyte imbalances, fatigue, sleep disturbances, paraneoplastic syndromes, pain (in later stages).

Tumour grading

• Use Microscopic/histologic examination
• Cells are classified on degree of differentiation and number of mitotic cells (Grade 1-4).

TNM Staging

• T = tumour size (1-4)
• N = lymph node involvement (0-3)
• M = metastasis (0-1)
• Cancer is confirmed through clinical, radiographic, and surgical examination.

Prevention

• Avoidance of environmental exposure
• Diet and lifestyle changes
• Products for personal care
• Vaccinations (HPV)
• Routine screening and checkups

Paraneoplastic syndromes

• Syndromes is unrelated to the initial tumour side
• Can be caused by Ectopic hormones or factors secreted by tumour cells

Seven Warning Signs of Cancer:

• Change in bowel/bladder habits.
• A sore that does not heal.
• Unusual bleeding or discharge.
• Thickening or lump.
• Indigestion or difficulty swallowing.
• Obvious change in wart/mole.
• Nagging cough or hoarseness

Cancer treatments

• Surgery
• Radiation therapy
• Chemotherapy
• Hormone and anti-hormone therapy
• Immunotherapy
• Targeted therapies

Cancer in New Zealand

• Growing & aging population
• About 1 in 3 people get cancer are cured
• Lung: Biggest cause of cancer
• Bowel: One of the highest rates

Diagnosing Cancer

• Skin Checks
• Pap Smear
• Colonoscopy
• Mammogram
• Blood Test
• Tissue Test

Skin Cancer

• High Rate in New Zealand
• Risk factor cumulative sun exposure
• Red, Scaly, Rough lesions on sun-exposed body parts

Clinical Description of Cancer

• Leading cause of deaths
• Caused from Lung, colon, breast, melanoma, prostate or cervical
• Caused by mutations in genes controlling cell growth
• Risk Factors including exposure to environmental carcinogens; diet.