ON1 Intro to oncology

What is cancer ? Cancer is a [blank_start]malignant[blank_end] tumor, a mass of cell in which cell division/cell cycle is no longer regulated. The tumor is [blank_start]benign[blank_end] if it does not spread (but may still cause tissue damage). The spread of a cancer to a secondary site is called [blank_start]metastasis[blank_end]. Some common carcinomas(a type of cancer that starts in cells that make up the skin or the tissue lining organs): - [blank_start]Lung, breast, colon, prostate, bladder[blank_end] Leukemias: - Blood stream Lymphomas: - Lymph nodes Some common sarcomas(a type of cancer that can occur in various locations in your body): -[blank_start]Fat, bone, muscle[blank_end]

Epidemiology: - Leading cause of [blank_start]death[blank_end] in NZ – 30.6%. - 70% of cases & deaths in [blank_start]>[blank_end]60 - [blank_start]Prostate[blank_end] most common in men, [blank_start]breasts[blank_end] most common in women - [blank_start]Lung[blank_end] cancer most lethal - Rates higher for those residing in [blank_start]more[blank_end] deprivedareas

Screening: Detects the possibility of cancer, is not [blank_start]definitive[blank_end]. Are often population based tests. Can be done at [blank_start]home[blank_end] or in clinics. Has [blank_start]variable[blank_end] sensitivity & specificity. E.g.: Prostate-specific antigen ([blank_start]PSA[blank_end]) testing, mammography, Pap smears, breast self examination, blood in stools, mole checks Diagnosis: [blank_start]confirmation[blank_end] of cancer. Can be done: with imaging - [blank_start]X-ray, CT, PET or MRI[blank_end], biochemical tests - tumor [blank_start]biomarkers[blank_end] in the blood e.g. carcinoembryonic antigen (CEA), or by [blank_start]biopsy[blank_end]. To grade the cancer, [blank_start]microscopy[blank_end].

Cancer Grading • grading system depends on that [blank_start]type[blank_end] of cancer • 4 [blank_start]or[blank_end] 10 point scale, higher number = [blank_start]worse[blank_end] • Low grade - normal tissue [blank_start]structure[blank_end], cells well differentiated • High grade – [blank_start]un[blank_end]differentiated, [blank_start]disorganized[blank_end] mass

Cancer Staging: Extent of tumor – how large, has it spread. Different methods • TNM: - Tumour – size, [blank_start]0 to 4[blank_end] - Nodes – local [blank_start]metastases[blank_end] to [blank_start]lymph[blank_end] node, number/location 0-4 - Metastases – 0 ([blank_start]no[blank_end] spread) or 1 (distant metastases) • Stage & grade used by oncologist, along with information on the patient age & health, to determine [blank_start]treatment options & prognosis[blank_end]

(Healthy) Cell cycle: • cell numbers are [blank_start]maintained[blank_end] at homeostasis in the body • cell turnover is different for different tissue types - most cells are [blank_start]terminally differentiated[blank_end] and are [blank_start]long[blank_end] lived. Exceptions - [blank_start]bone[blank_end] marrow, [blank_start]mucosal[blank_end] surfaces, skin. • cell is formed by [blank_start]division[blank_end] (by mitosis), functions, wears out, [blank_start]dies[blank_end] (apoptosis) • in homeostasis division is [blank_start]equal to[blank_end] apoptosis In a tumour division is [blank_start]greater than[blank_end] apoptosis.

The cell cycle is carefully regulated and there are a number of checkpoints. The cell must check that all necessary [blank_start]enzymes[blank_end] etc, are present, and also for DNA integrity and [blank_start]damage[blank_end] (mutations). If DNA damage is present, the cell should [blank_start]not[blank_end] enter cell cycle ([blank_start]G1 arrest[blank_end]) or mitosis is delayed until damage is repaired ([blank_start]G2/Marrest[blank_end]). If DNA damage is not repaired [blank_start]apoptosis[blank_end] is initiated - this is a [blank_start]key[blank_end] regulatory pathway . Genes/proteins involved include p53, Bax, and Rb. If these genes are mutated, the checkpoints are removed and damaged cells can [blank_start]proliferate[blank_end]…. and a tumour can develop. • [blank_start]p53[blank_end] is mutated in > 70% of tumours

Telomeres • Are an internal divisional [blank_start]clock[blank_end] that regulates the replicative lifespan of a cell • They are non-[blank_start]coding[blank_end] repetitive DNA located at the [blank_start]ends[blank_end] of all chromosomes, with each division telomeres [blank_start]shorten[blank_end] & when they reach a threshold - cell is targeted for [blank_start]apoptosis[blank_end] • Tumours prevent this by [blank_start]stabilising[blank_end] telomere length by activating [blank_start]telomerase[blank_end] (80-95% of tumours)

Uncontrolled cell [blank_start]division[blank_end] differentiates cancerous cells from healthy cells and so it is a good drug [blank_start]target[blank_end]. • Some drugs act in: - specific [blank_start]phases[blank_end] of cell cycle ([blank_start]time[blank_end] dependent mechanism of action) Others not cycle–specific ([blank_start]concentration[blank_end] dependent).

Label the process of metastasis from start (1) to finish (8) 1. [blank_start]tumor cells proliferate[blank_end] (cell cycle unregulated) 2. avoid [blank_start]immune system recognition[blank_end] (ON02) 3. [blank_start]tumor must vascularise[blank_end] (angiogenesis) 4. [blank_start]local[blank_end] invasion 5. penetration of [blank_start]blood[blank_end] vessel 6. spread - accumulation of cells in [blank_start]small vessels[blank_end] 7. [blank_start]exit[blank_end] from the vessels 8. [blank_start]invasion and proliferation[blank_end]

Vascularisation/Angiogenesis is necessary to supply [blank_start]oxygen[blank_end] and nutrients for [blank_start]growth[blank_end] of the tumour. • Multiple factors used/pathways means [blank_start]low efficacy[blank_end]/short term nature of anti-angiogenic therapies • Also get development of new [blank_start]lymphatic[blank_end] vessels (lymphangiogenesis) • New vessels (blood & lymphatic) that develop are [blank_start]leaky & inefficient[blank_end]

Spread: • Cells move towards vessels in response to [blank_start]oxygen & nutrients[blank_end] • Enter into [blank_start]leaky[blank_end] new vessels, or acquire [blank_start]mutations[blank_end] (mostly unknown) to breach intact vessels • Once in vessel they need to survive factors such as physical [blank_start]shear[blank_end] stress & [blank_start]platelet[blank_end] adhesion • Getting out – adhesion [blank_start]receptors[blank_end] • Local lymph nodes (new lymphatic vessels) Spread can be distant. - Mechanical lodging – platelet + tumour cell [blank_start]aggregates[blank_end] get lodged in small [blank_start]capillaries[blank_end]

Growth of Metastasis" • After extravasation many tumours can not grow/thrive (are [blank_start]dormant[blank_end]) Why? • No [blank_start]angiogenesis[blank_end] • Some can’t enter back into cell [blank_start]cycle[blank_end] Knowledge of these angiogenic [blank_start]pathways[blank_end] allows for development of new molecular [blank_start]target[blank_end] therapies. However – drug [blank_start]resistance[blank_end] is an issue. Metastatic cells are less [blank_start]genetically[blank_end] stable. Not all primary tumours, or cells in the primary tumour, can [blank_start]metastasize[blank_end] (will be benign). Some cancers can be [blank_start]cured[blank_end], others are treatable.