Session 9: Invasion & Metastasis and the Effects of Neoplasms

Neoplasm

Abnormal growth of cells that persists after the initial stimulus is removed

Malignant neoplasms

An abnormal growth of cells that persists after the intial stimulus is removed and invades surrounding tissue with potential to spread to distant sites

Neoplasia

An irreversible disorder of cell growth, triggered by series of mutations (germline, acquired/somatic) affecting a single cell and its clonal progeny.

The causative mutations give neoplastic cells a survival and growth advantage.

The result is excessive & autonomous proliferation (independent of physiological growth signals).

Tumour

Any clinically detectable lump or swelling.

A neoplasm is just ONE type of tumour.

Cancer

Any malignant neoplasm

Metastasis

Malignant neoplasm that has spread from its original site to a new non-contiguous site. The original position is the primary site and the place to which it has spread is a secondary site.

Dysplasia

Pre-neoplastic alteration in which cells show disordered tissue organisation. It is not neoplastic because the change is reversible.

Cell maturation and differentiation are delayed

Example of a non-neoplastic tumour

Abscess

Haematoma

Keloid scar

Epidermoid cyst

Benign neoplasms nomenclature

Benign neoplasms end in -oma

Malignant neoplasms nomenclature

Epithelial malignant neoplasm (90%) end in -carcinoma

Stromal malignant neoplasm end in -sarcoma

Carcinomas can be in-situ or invasive. What do these terms mean?

In-situ = no invasion of basement membrane

Invasive = invasion of basement membrane

Give some examples of benign epithelial neoplasms

Stratified squamous = squamous papilloma

Transitional = transititional cell papilloma e.g., bladder mucosa

Glandular = adenoma e.g., adenomatous polyp of colon

Give some examples of (CARCINOMAS) malignant epithelial neoplasms

Stratified squamous epithelium (e.g., skin, mouth, cervix) = squamous cell carcinoma

Glandular epithelium (e.g., stomach, colon, lung, prostate, breast, kidney, pancreas) = adenocarcinoma

Transitional epithelium (e.g., bladder, ureter, renal pelvis) = transitional cell carcinoma or urothelial carcinoma

Others = basal cell carcinoma

Benign neoplasm of connective tissues

Fibrous tissue

Fibroma

Benign neoplasm of connective tissues

Smooth muscle

Leiomyoma

Benign neoplasm of connective tissues

Striated (skeletal) muscle

Rhabdomyoma

Benign neoplasm of connective tissues

Bone

Osteoma

Benign neoplasm of connective tissues

Cartilage

Chondroma

Benign neoplasm of connective tissues

Fat

Lipoma

Benign neoplasm of connective tissues

Nerve/nerve sheath

Neuroma, neurofibroma

Benign neoplasm of connective tissues

Glial cells

Glioma

Sarcomas, malignant neoplasm of connective tissues

Fibrous tissue

Fibrosarcoma

Sarcomas, malignant neoplasm of connective tissues

Smooth muscle

Leiomyosarcoma

Sarcomas, malignant neoplasm of connective tissues

Skeletal muscle

Rhabdomyosarcoma

Sarcomas, malignant neoplasm of connective tissues

Bone

Osteosarcoma

Sarcomas, malignant neoplasm of connective tissues

Cartilage

Chondrosarcoma

Sarcomas, malignant neoplasm of connective tissues

Fat

Liposarcoma

Sarcomas, malignant neoplasm of connective tissues

Nerve sheath

Neurofibrosarcoma

Neoplasms of lymphoid tissue

Lymphoma

Where do lymphomas occur

Occurs in lymphoid tissue, usually in lymph nodes but can also be found in extranodal locations e.g., skin, salivary glands, GI tract

Example of lymphoma

Hodgkin's lymphoma

Germ cell neoplasms

Testis

Teratoma (benign and malignant)

Seminoma

Embryonal cell carcinoma

Ovary

Usually benign

Mature cystic teratoma

Dermoid cyst

Struma ovarii

Neuroendocrine tumours (NET)

Well differentiated = carcinoid tumour

Poorly differentiated = small cell lung carcinoma

Phaeochromocytoma (adrenal, most benign)

-Blastoma tumours

Arise from precursor cells and are composed of cells with immature characteristics seen in developing (embryonic) stages

Melanoma

Malignant tumour of cells derived from neural crest

Mesothelioma

Tumour of mesothelium (malignant)

Benign neoplasm features

- Confined to site of origin

- Do not produce metastases

- Well-defined, rounded pushing outer edge (pushing outer margin)

- With capsule or pseudocapsule

- Microscopically resemble the tissue of origin (they are well differentiated)

Malignant neoplasm features

- Irregular outer margin & shape

- May show areas of ulceration/necrosis

- Range from well to poorly differentiated

- Microscopically do not resemble the tissue of origin (clinicians use 'grading' to indicate the level of differentiation)

- Potential to metastasise

- Loss of contact inhibition

- Abnormal mitotic figures

High-grade cancer

Grade III/IV

Poorly differentiated, or anaplastic tumor. Very pleomorphic cells, little or no keratin, difficult to identify, enlarge rapidly, metastasizes early

Low-grade cancer

Grade I

Well-differentiated tumor closely resembles tissue of origin, grows slower and metastasizes later

Anaplastic

Undifferentiated cell growth - without form (bizarre)

Cells with NO resemblance to ANY tissue (very poor differentiation)

Dysplastic conditions

Example of oesophageal dysplasia

Barrett's with dysplasia

Dysplastic conditions

Example of epithelial dysplasia

Epithelial dysplasia of the cervix (CIN)

Dysplastic conditions

Example of colon dysplasia

Adenomatous polyps

What is the most lethal ability of malignant cells?

Ability of malignant cells to spread (metastasise) to distant sites leads to a greatly increased tumour burden with local & distant tissue destruction/damage

Process of invasion and metastasis of malignant cells

1) Grow and invasion at primary site

2) Enter transport system e.g., lymphatics/blood and lodge at a secondary site

3) Grow at secondary site to form a new tumour. At all points, the cells must evade destruction by immune cells, which depending upon the aggressiveness of the tumour - immune system may or may not be effective

The colorectal polyp to cancer progression model

A collection of cells is known as 'monoclonal' if they all originated from a single founding cell.

How do we know that neoplasms are monoclonal?

Evidence that neoplasms are monoclonal came from the study of X-linked gene for the enzyme glucose-6-phosphate dehydrogenase (G6PDH) in tumour tissue from women

The gene has several alleles encoding different isoenzymes.

Early in female embryogenesis, one allele is randomly inactivated in each cell (lyonisation).

in heterozygous women that happen to have one allele encoding a heat stable isoenzyme and one heat labile isoenzyme, normal tissues will be a patchwork of each type.

However, neoplastic tissues only express ONE isoenzyme, indicating a monoclonal group of cells.

Invasion of cancer involves three important alterations which collectively create a carcinoma cell phenotype which appears more like a mesenchymal cell than an epithelial cell (EPITHELIAL TO MESENCHYMAL TRANSITION; EMT)

What are these three alterations?

1) Altered adhesion

Reduction in E-cadherin

Altered adhesion between malignant & stromal proteins involves changes in integrin expression.

2) Stromal proteolysis

Cells must degrade BM & stroma to invade successfully (proteases, matrix metalloproteinases; MMPs)

3) Altered motility

Altered motility involving change in actin cytoskeleton.

Signalling via integrins is important and occurs via small G proteins such as members of the Rho family.

The growth of cancer cells at a secondary site is known as ___

Colonisation

Malignant cells can be transported to distant sites via three routes, what are they?

What are the three routes of metastatic spread?

1) Blood vessels via capillaries/venules

2) Lymphatic vessels

3) Fluid in body cavities (pleura, peritoneal, pericardial, brain ventricles) = transcoelomic spread

Micrometastases

Many malignant cells lodge at secondary sites, but these tiny cell clusters often die or fail to grow into clinically detectable tumours.

Surviving microscopic deposits that do NOT grow are called micrometastases.

Describe the main steps involved in invasion of the ECM by tumour cells

1) Detachment of tumour cells from one another by unzipping of the anchor protein E-cadherin

2) Degradation of the ECM by collagenase which attacks the collagen fibres of the basement membrane

3) Loss of adhesion of cells from integrins

4) Migration of tumour cells through ECM

Stromal invasion involves three important alterations which are...

1) Cells degrade basement membrane & stroma using proteases (matrix metalloproteinase; MMP).

2) Malignant cells take advantage of other nearby non-neoplastic cells = which forms cancer niche. Normal cells provide growth factors/proteases that help cancer thrive.

3) Altered motility involves changes in actin cytoskeleton.

Circulating Tumour Cells (CTCs)

Tumor cells that have passed from tumor into blood; primary; place in research

How can CTCs be detected? What are the main methods of detection?

Flow cytometry

CellSearch system

High-def fluorescence scanning microscopy

Size sorting

Fibre optic/laser scanning techniques

Why is detection of CTCs useful?

May aid an earlier diagnosis, prognosis, prediction, stratification & pharmacodynamics

Tumour dormancy

When a malignant neoplasm relapses years after an apparent cure, it is typically due to one or more micrometastases starting to grow.

At the secondary site, malignant cells must get out of the vessel (___) and then grow to form a clinical metastasis. This is a dynamic process, involving ___, vascular ___ and endothelial ___

At the secondary site, malignant cells must get out of the vessel (extravasation) and then grow to form a clinical metastasis. This is a dynamic process, involving adhesion, vascular migration and endothelial remodelling (Twist gene)

What are the triggers for the development of a metastasis from a micrometastasis?

Complex process - not fully understood.

There must be an alteration in...

1) Microenvironment (soil) becoming more favourable

2) Immune status

3) Angiogenic switch

The site of a secondary neoplasm depends on two factors - what are they?

1) Regional drainage

Lymphatic metastasis usually spreads to lymph nodes

Transcoelomic spread usually spreads to other areas in coelomic space or adjacent organs

Bloodborne metastases spread to next capillary bed encountered

2) Seed-and-soil phenomenon

This can explain the unpredictable distribution of blood-borne metastases and is often due to interactions between malignant cells & local tumour environment (the niche) at the secondary site.

Carcinomas typically spread via...

Lymphatics

Sarcomas typically spread via...

Bloodstream

Neoplasms that most frequently spread/metastasise include...

Breast

Bronchus

Kidney

Thyroid

Prostate

Common sites of bloodborne metastasis include...

Lung

Bone

Liver

Brain

GI tract malignancies and melanoma tend to spread to...

Liver

Sarcomas and renal cell carcinoma tend to spread to...

Lung

Malignant neoplasms have personalities

Some malignant neoplasms are more aggressive and metastasise very early e.g., small cell bronchial carcinoma

Others almost never metastasise e.g., basal cell carcinoma (BCC) of the skin

Describe some of the DIRECT and LOCAL effects of neoplasms

1) Direct invasion/destruction of normal tissue

2) Ulceration at surface leading to bleeding

3) Compression of adjacent structures (e.g., in benign tumours)

4) Blocking tubes/orifices

Describe some of the INDIRECT SYSTEMIC effects of neoplasms...

- Paraneoplastic syndrome (release of hormones from tumour)

- Reduced appetite

- Cachexia (weight loss)

- Malaise

- Immunosuppression

- Thrombosis

Malignant tumours can often produce hormones leading to a paraneoplastic syndrome.

Give examples of tumours that can do this.

1) Bronchial squamous cell carcinoma = PTH-like hormone

2) Bronchial small cell carcinoma = ACTH or ADH

Miscellanous systemic effects of neoplasms...

1) Neuropathies affecting brain/peripheral nerves

2) Skin problems e.g., pruritus, abnormal pigmentation

3) Fever

4) Myositis

5) Finger clubbing

Benign neoplasms of endocrine glands are well differentiated and so typically produce hormones.

Give an example of a benign neoplasm that does this

A thyroid adenoma produces thyroxine

Contact inhibition

A process that stops additional cell growth when cells become crowded

Healthy cells stop dividing when it becomes crowded

Features of adenocarcinomas

- May produce mucin

- Can occur in thyroid gland

- Form glandular acini

- Contain intracytoplasmic cytokeratin

Features of dysplasia

- Loss of normal maturation

- Pleomorphism

- Increased mitotic activity

- High nuclear/cytoplasmic ratio

Tumours of soft tissues...

- More often benign (lipomas and leiomyomas)

- Are classified by tissue of origin

- If malignant, are referred to as 'sarcomas'

Some examples of malignant tumours

Multiple myeloma

Osteosarcoma

Lymphoma

Common sites of metastasis

Brain, liver, bone marrow

Cancer cells are posed with challenges in the circulation such as...

- Shear force

- Turbulence of blood flow

- Surveillance & attack from immune cells (NK cells)

- Lack of substratum

- Entrapment in capillary bed

Describe some ways in which cancer cells OVERCOME these challenges

Release of coagulation factors which form an outer platelet shield which eventually forms a tumour platelet microthrombi which protects cancer cells from shearing & turbulence forces

This prevents immune detection using platelet derived MHC class I coating

Differentiation

When cells progress from stem cells to fully mature cells, they differentiate into the fully mature cell of that tissue.

A benign neoplasm has cells that closely resemble the parent tissue = they are well differentiated.

Malignant neoplasms range from well to poorly differentiated.

Cells with NO resemblance to any tissue = anaplastic.

A fully evolved malignant neoplasm exhibits six hallmarks of cancer and two enabling features.

What are they?

Six Hallmarks of Cancer

1) Self-sufficiency in growth signals

2) Resistance to stop signals

3) Cell immortalisation

4) Sustained angiogenesis

5) Resistance to apoptosis

6) Ability to invade and produce metastases

Two Enabling Features

1) Genomic instability

2) Inflammation (local chronic inflammation and angiogenic steal)