Cellular Basis of Cancer

Dr Rosemary Bassrosemary.bass@northumbria.ac.uk

•Causes of cancer

Last session

•History

•Terminology used to discus cancer

• Incidence Rates

•Cancer Types

•How cells change their nature during cancer progression

•Tumour Growth

Content of this lecture

•Cell Growth / Cell Cycle

•Cancer Progression

•Benign vs Malignant Tumours

• Invasion, Angiogenesis and Metastasis

•Clinical Symptoms and cancer staging

•Diagnosis and Treatment

• cancer also a cellular disease

• mechanisms of normal cell growth control important

• understanding normal cell growth controls may provide therapeutic targets

Cancer and Cell Growth

• cancer is a genetic disease

• cancer studies have also elucidated normal cell growth mechanisms

Mitosis

S Phase

G1G2 G0

Cell Cycle

= major checkpoints

• allow progression to next phase of cell cycle

• cyclins - proteins associated with each phase of cell cycle

• cyclin-dependent kinases (Cdks) - activate or regulate proteins critical for each stage of cell cycle

Cell Cycle Checkpoints

7

Control system co-ordinates cycle

Key control proteins:

Cyclin dependent kinases + cyclins(CDK or CDC)

Cyclins bind CDKs - affect their ability to phosphorylate serine & threonine residues of their substrates

8

Checkpoints

Activity and levels of cyclin/CDK complexes govern these checkpoints

G1/S progressionRb, Myc also important

G2/Mnot completely understood

9

M MG2SG1

Cyclin BR point

Nuclear D1

Cyclin E

Cyclin A

Cyclins ctd.

De-regulation of cyclins associated with cancer

10

Restriction or R point

Deregulation of R point decision making machinery accompanies formation of most types of cancer cells

Commitment to replicate chromosomes, differentiate or enter apoptosis

• growth Factors (GFs)eg. epidermal growth factor (EGF)eg. insulin-like growth factor I (IGF I)

• hormoneseg. thyroid hormones (T3, T4)

• cell anchorage and adhesion

• contact / density inhibition

General Controls of Cell Growth

• nutrient supply (vascularisation)

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Tumour Cell Population Doublings 0 10 20 30 40

108 cells (visible on X-ray)

109 cells (palpable)

1012 cells (patient death)

Tumour Growth Rate

Clonal Growth of Tumour Cells

Clonal Growth of Tumour Cells (2)

new sub-clones may grow

How do you detect cancer?

Cervical dysplasia (1)

• normal cervical squamous epithelium with dysplastic squamous epithelium

normal

dysplastic

http://medlib.med.utah.edu/WebPath

Cervical dysplasia (2)

• normal / dysplastic border in cervical squamous epithelium - cells become more disorderly

norm

aldysplastic

http://medlib.med.utah.edu/WebPath

Cervical neoplasiaN

eosplastic infiltration

http://medlib.med.utah.edu/WebPath

• microscopic appearance of cervical neoplasia

• the neoplasm is infiltrating the underlying cervical stroma

• cancer progression occurs in stages

- dependent on cancer promoters

• benign tumours

Cancer Progression

• malignant tumours

• evidence in some tumours (eg. GI) of progression from benign to malignant

- eg. free radicals / radiation / mutagens

• sub-clones with growth advantage become:

Cancer Progression - Colon

http://www.eurogene.org/etext/cancgen/img/Fodde2/image003.jpg

Benign Malignant

•mitoses few, normal many, abnormal

Benign vs Malignant - Rapid Growth

•nuclei normal large, irregular

•necrosis/ never extensivehaemorrhage

Benign Malignant

•morphology close to variable normal poor

Benign vs Malignant (2) - Differentiation

• function often retained, lost retained or abnormal

products

Benign Malignant

•capsule often intact missing broken

Benign vs Malignant (3) - Boundary

• invasion absent (v. rare) frequent

•metastasis never frequent

• expanding tumour able to grow into tissue spaces and cavities

Invasion

• malignant tumours invade normal tissues

http://www.ma.hw.ac.uk/~jas/researchinterests/cancerinvasion.html

normal cervix

cervical carcinoma

invasive process beginning

• understanding molecular mechanisms of cancer progression

most cancer deaths caused by metastatic tumours

• understanding of molecular mechanisms involved in metastasis important

Discovering New Treatments for Cancer

• understanding molecular mechanisms of cancer initiation

depends upon:

Invasion and Metastasis

• tumour cell produces enzymes / growth factors

Steps in Metastasis

• most steps are active processes

• similar to normal tissue modelling / wound healing

enzymesinhibitor proteins

growth factors

• invasion of surrounding tissue + invasion of blood or lymph vessel

Steps in Metastasis

• cell detachment from tumour mass

- lectins- cadhedrins

Important Proteins in Metastasis

• cell Adhesion Molecules (CAMs)

• extracellular Matrix (ECM) proteins

- collagen, fibronectin etc interact with- integrins on cell surface

• all involved in normal tissue organisation / stability

• interacting proteins must be overcome / digested by metastatic cancer cell

Steps in Metastasis

• survival of conditions in blood or lymph

• most cells die after a few hours due to:

- mechanical stress- lack of essential nutrients- high oxygen toxicity- destruction by immune cells

Steps in Metastasis

• attachment to endothelial cells in capillaries at remote site

• extravasation of tumour cell through vessel wall

Extravasation

- metalloproteinases- cathepsins etc

Important Proteins in Metastasis (2)

• proteolytic enzymes

• new growth stimulators

- growth factors (+ receptors)- hormones

• stimulators of vascularisation

- more growth factors (eg. GF stimulates capillary growth)

Steps in Metastasis

• growth / survival as secondary tumour

• stimulation of new blood supply

Primary Common Sites of Tumour Metastasis

•gastrointestinal livercarcinoma

Typical Metastatic Spread Patterns

•melanoma liver, brain, bowel

•prostatic carcinoma bone

•small-cell lung brain, liver, carcinoma bone marrow

•breast bone, brain, liver, carcinoma adrenal, lung

Angiogenesis

http://www.angio.org/img/cascade_image.jpg

Angiogenesis Steps

1. angiogenic growth factors (GFs) diffuse into nearby tissues

2. GFs bind to specific receptors on endothelial cells (EC) of nearby blood vessels

3. & 4. endothelial cells activated - produce enzymes that dissolve tiny holes in vessel membrane

5 - 10. ECs proliferate through holes towards tumour, form tubes and loops - become stabilised by smooth muscle

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Tumour Cell Population Doublings 0 10 20 30 40

108 cells (visible on X-ray)

109 cells (palpable)

1012 cells (patient death)

Tumour Growth Rate

TUMOUR MARKERS: aim to detect tumours as early as possible

Biomarkers

“A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Also called molecular marker and signature molecule”

National Cancer Institute

Tumour Markers

Proteins↑↓ regulated in the progression of cancer

Some specific for one type of cancer, others for >1 type

Potential for screening/prognosis/efficacy of treatment

Blood/saliva/urine vs. biopsy

No routine screening in UK

Classes of Tumour Marker

• Oncofetal proteins

- α-fetoprotein germ cell tumours

primary liver cancer

- CA-125 ovarian cancer

- human chorionic choriocarcinoma

gonadotrophin (hCG) teratoma

• Placental Products

- placental alkaline ovarian cancer phosphatase testicular cancer

• Ectopic Hormones

- adrenocorticotrophic bronchus carcinoma hormone (ACTH)

- calcitonin thyroid cancer

- prostate-specific prostate cancer

antigen (PSA)

• Tissue-specific Antigens

- thyroglobulin thyroid cancer

Classes of Tumour Marker

• Enzymes

- alkaline phosphatase osteosarcoma

- prostatic acid prostate cancer phosphatase

- IgG IgA IgD IgE myeloma

• Immunoglobulins

- Bence-Jones protein myeloma (free κ and λ chains)

- lactic dehydrogenase neroblastoma

Classes of Tumour Marker

Cancer Treatment

• surgery

- principal treatment

- effective local control

- best before tumour spread

- invasive

- may involve risky procedures

http://www.cooperhealth.org/content/MinSurg_Cancer.asp

Cancer Treatment

• Chemotherapy

- body-wide drug delivery

- potential to eliminate metastatic cells

- damaging effects on healthy cells

http://www.ucsf.edu/dpsl/chemo.html

Cancer Treatment

• Radiotherapy

- effective local control

- whole body radiotherapy possible (eg. for lymphomas)

- often used to reduce tumour size prior to surgery

http://www.hnsaonline.com/iort.htm

Radiotherapy

• External Beam

- X-rays from linear accelerator

• Radioactive Implants

- gives very high local dose

- pellets or needles of Yttrium-90

- γ rays from radio-cobalt

http://www.ncrc.ac.yu/onkoeng/odelenja/images/

News Flash!

• doses ~500000 times greater than for medical imaging

Effects of Radiotherapy

• both methods use ionising radiation

• cause many double-strand breaks in DNA

• cells cannot repair DNA and die

• normal cells often recover more quickly than tumour cells

100% cure rare - data shown as 5-year survival

• highly variable, vague or none

• early medical attention improves prognosis

• general symptoms - 1 or more of:

Clinical Symptoms of Cancer

- weakness- breathlessness- weight loss- bleeding- pain (when tumour presses on nerves,

internal organs or erodes bone)

• lump detectable if tumour on or near surface

• clinical investigations:

Clinical Symptoms of Cancer

- physical examination- imaging:

radiography CT (computerised tomography) ultrasound radioisotope scanning MRI (magnetic resonance imaging)lymphography

- biopsy pathologist

Cancer Staging (TNM) eg. lung cancer

Cancer Staging - Primary Tumour

Tis in situ, non-invasive

T1 small, minimally invasive within primary organ site

T2 larger, locally invasive within the primary organ site

T3 moderate size and/or invasive, spread to adjacent lymph nodes

T4 very large and/or very invasive, metastatic spread to distant organs

Cancer Staging - Lymph Nodes and Metastases

N0 no lymph node involvement

N1 regional lymph node involvement

N2 extensive regional lymph node involvement

N3 distant lymph node involvement

M0 no distant metastases

M1 distant metastases present