2. Tumour Growth & Metastases

proto-oncogenes

code for proteins that promote cell cycle progression → mutate to become oncogenes

• have potential to cause cancer

• stimulate

  • cell division

  • cell differentiation

  • halt cell death

• eg. growth factors (receptors), signal transduction proteins, transcription factors, proteins that inhibit apoptosis

tumour suppressor genes (TSG)

normal growth suppressor genes

• limit cell division

• promote apoptosis (cell death)

• repair defective DNA

• eg. TP53 - found on chromosome 17

  • blocks proliferation in G1 (growth 1 - phase of cell cycle)

  • apoptosis

  • DNA repair

• 1 normal gene inherited = predisposed to cancer

two-hit hypothesis

need loss-of-function in both copies of proto-oncogene/tumour suppressor gene to cause cancer

• 1 functioning copy is enough to present normal phenotype

mutations

• translocation

  • chromosome damaged in one area

  • fixing machinery swaps damaged areas of 2 different chromosomes

• gene amplification

  • mutation can result in higher amount of proteins than necessary

• point mutation

  • one codon deleted/mutated + replaced by wrong one

  • can sometimes function normally, other times results in mutated protein

doubling time

time taken for tumour to double its volume

• takes about 1-3 months for humans

  • varies b/w different tumour type

sub-clinical disease

disease that may escape detection (0.5-1cm³) until it causes clinical symptoms

• many tumours have long subclinical period

  • may allow for metastasis prior to detection, eg. small cell lung cancer

• early treatment might reduce but not eliminate risk of metastasis → screening

• to palpate tumour, must measure at least 1cm³

  • 1 billion cells or 30 doublings

growth fraction

fraction of cells that are proliferating

• most tumours contain non-proliferating cells = support cells

• some tumour cells may have lost capacity to divide

  • differentiation

  • biological change

  • change in micro-environment (pH, oxygenation, nutrition)

• other cells in population continue dividing, while others stop

cell loss

rate at which cells are shed from tumour

• necrosis

• metastasis

• continuous shedding of cells + cells failing to mature + cell death = 80-90% of loss of replicating cell pool

  • why it may take many years for 1cm mass to form

local spread (direct extension)

direct extension + invasion along tissue planes

• common method of spread

• invades + destroys local surrounding normal tissue

  • eg. prostate cancer spread to bladder wall

• causes compression, ulceration, pain, bleeding, swelling

• surgical implications → if surgery can be performed must include margin of normal tissue to limit local recurrence

transcoelomic spread

cancer cells break out of original site + carried in peritoneal fluid

• uncommon method of spread

• challenging to treat

  • disseminated growth (scattered)

  • overproduction of ascitic fluid

• peritoneal cavity

  • spread across peritoneal surface from one organ to another

    • eg. stomach → ovary

• pleural cavity

  • spread of primary lung cancer or metastatic cancer across pleura from one lung to another

ascites

collection of fluid in abdomen

• contains proteins + growth factor

• provides environment for malignant cells to grow w/o attachment = anchorage independent

• overproduction can be caused by metastasis → requires draining

• in lungs = pleural effusion

lymphatic spread

lymphatic vessels do not have basement membrane → easy to enter + can pass cancer cells to blood stream

• most common method of spread

• lymph travels via lymphatic vessels to subclavian vein → SVC → bloodstream

  • cancer cells can break tumour + enter lymphatic vessel → enter bloodstream = hematogenous spread

fixed node

refers to cancer in lymph node that has grown beyond capsule to surrounding tissue

• cancer cell has gotten into lymph node → attached to node → grown beyond to surrounding tissue = cancer progression = bad

  • higher risk of getting cancer to other parts of body

sentinel node

first lymph node in path of lymph drainage from primary tumour

• biopsied to assess for lymphatic spread

sentinel lymph node biopsy

1. radioactive dye injected into area of interest to locate sentinel node

2. sentinel node removed + examined

3. negative = no cancer cells → rest of lymph nodes in area unlikely to contain cancer

4. positive = cancer cells found → more lymph nodes from area may be removed to check for spread

hematogenous spread

blood vessels provide least difficult barrier of entry + exit for cancer cells

• common method of spread

• capillaries constructed from single layer of endothelial cells

  • built for passage of materials + fluids

    • arteries more difficult to spread through b/c of smooth muscle layer

• circulation plays role in sites of metastatic growth

  • liver + lung = common metastasis sites

    • lung → blood returning to heart from upper + lower body passes lungs for reoxygenation

    • liver → blood from intestines travel through hepatic portal vein before traveling to heart

leptomeningeal spread

spread through cerebrospinal fluid (CSF)

• very uncommon method of spread

• CSF surrounds brain + spinal cord

  • specific to neural tumours (brain + spine)

    • if tumour from brain/spinal cord were to pass to other organs/parts of body → need to pass BBB

• eg. medulloblastomas of brain often seed (spread) into spinal canal via CSF

first-pass organ

first organ encountered by cells frequently supports secondary tumour growth

• main organs:

  • heart

    • metastasis very difficult → not conducive environment for cancer cell growth

      • hard for cells to latch on + stay

      • thick muscle + connective tissue

      • thicker walls, hard for cells to break through

    • blood flows from heart to lungs where metastasis frequently occurs

  • liver

    • accessible to cancer cells due to lack of barriers b/w sinusoids + hepatocytes

seed and soil theory

metastasis required for cancer cells (seeds) + correct environment (soil) in which to grow

• soil = tissue in which appropriate factors could be recognized by cancer cell receptors providing homing mechanism

• most cells destroyed in transit or cannot survive new environment

angiogenesis

formation of new blood vessels

• initial growth of tumour is close to existing blood vessels (1mm)

• tumour grows → more cells required more nutrients + oxygen supplied by blood

• success of tumour induced blood vessel formation → dictates if metastasis will remain dormant or grow larger than 1mm

• cancer cells secrete signalling molecules → stimulate proliferation of endothelial cells → secrete proteases causing capillary sprouts to form = new capillary bed

• liver + lung = common metastasis sites

• cancer-induced growth disorganized + not well-structured

  • leaky + unstable

    • large tumours can be bleeding

  • radiation can cauterize bleeding

radical (curative) treatment

potential to completely cure patient of cancer

• if cancer is widespread, may need chemotherapy treatment

palliative (symptom management) treatment

deal w/ symptoms

• if cancer is widespread throughout body + cannot be cured

lung primary site

common metastatic sites

• liver

• adrenal gland

• bone

• brain

breast primary site

common metastatic site

• lung

• bone

• brain

stomach primary site

common metastatic site

• liver

anus primary site

common metastatic site

• liver

• lungs

bladder, cervix, and prostate primary site

common metastatic site

• lungs

• bone

• liver

colorectal primary site

common metastatic site

• liver

• lung

• peritoneum

uterus primary site

common metastatic site

• bone

• liver

• lung

• peritoneum

• vagina

melanoma primary site

common metastatic site

• bone

• brain

• liver

• lung

• skin/muscle