Session 8: Neoplasm

Neoplasm

Newly formed collection of cells resulting from abnormal cellular proliferation that persists after the stimulus is removed

Benign tumours

Self-contained and localised with well-defined perimeters. They grow slower from a central mass.

Benign masses can be dangerous when they compress surrounding tissue as they can restrict blood flow to an area, leading to an impact on the function.

Malignant tumours

Not self-contained, do not compress surrounding tissue. Their growth is an irregular invasion of adjacent cells. They are capable of rapid growth. These tumours are not localised in metastasis (when they shed cells which travel through the blood to infect other tissues).

Metastasis

The spread of cancer cells to locations distant from their original site.

Give an example of a benign neoplasm that is medically important

1) UTERINE FIBROIDS

The development of fibroids increases with age and causes pain, excess menstrual bleeding or infertility

2) MENINGIOMA

Most frequently reported primary CNS tumour.

Aetiology of cancer

Combination of intrinsic and extrinsic factors account for cancer risk.

INTRINSIC

- Heredity

- Age

- Gender

- Sex

- Family history

- Genetic mutations

EXTRINSIC

- Chemicals

- Radiation

- Infections

About 30% of cancer deaths is due to the five leading behavioural/dietary risk factors, which are...

1) High BMI

2) Low consumption fruit/vegetables

3) No physical exercise

4) Smoking

5) Alcohol

Extrinsic factors which contribute to cancer aetiology are classified into three groups...

1) Chemicals

2) Radiation

3) Infections

Give some examples of chemical carcinogens

1) Polycyclic aromatic hydrocarbons (PAHs) e.g., Benzopyrene

2) Aromatic amines e.g., 2-napthylamine

3) Nitrosamines e.g., sodium nitrite

4) Asbestos

Give an example of a nitrosamine which is an industrial carcinogen used in the dye manufacturing process

2-napythylamine

Malignant neoplasms caused by the nitrosamine 2-napythylamine showed that...

- There is a long delay between carcinogen exposure & onset of malignancy

- Risk of cancer depends on the total carcinogen dose

- Sometimes organ specificity for particular carcinogens

Most carcinogens enter the body in the form of ___, before being converted to carcinogens by cellular machinery. An example of one of these carcinogens is ___.

Most carcinogens enter the body in the form of procarcinogens, before being converted to carcinogens by cellular machinery. An example of one of these carcinogens is benzopyrene.

Benzopyrene is a procarcinogen. It is one of the main carcinogenic agents in ___. It must be first oxidised by cytochrome ___ and further modified by other enzymes to become benzopyrene ___ ___ which binds covalently to DNA to form an ___ where it causes mutations.

Benzopyrene is a procarcinogen. It is one of the main carcinogenic agents in cigarettes. It must be first oxidised by cytochrome P450-1A1 and further modified by other enzymes to become benzopyrene diol epoxide which binds covalently to DNA to form an adduct where it causes mutations.

Initiator chemical carcinogens

Mutagens

Promoter chemical carcinogens

Cause prolonged proliferation in target tissues

The Ames test shows that...

Initiators are mutagens

Promoters cause prolonged proliferation in target tissues

The mutant monoclonal collection of cells becomes fully malignant via a process called ___

Progression

Carcinogens that act as BOTH the initiators and promoters are called ___ ___

Carcinogens that act as BOTH the initiators and promoters are called complete carcinogens

UV light penetration

It cannot penetrate deeper than the skin

Ionising radiation

Any form of radiation that has the ability to remove electrons from atoms and molecules

Examples

X-rays

Nuclear radiation

Nuclear radiation

Particles or electromagnetic radiation emitted from the nucleus during radioactive decay

Includes alpha particles, beta particles and gamma rays

Radiation can damage DNA directly and indirectly by producing ___ ___

Radiation can damage DNA directly and indirectly by producing free radicals

Most important type of radiation type is...

Ultraviolet radiation

Because we are exposed to this type of radiation daily from sunlight - increased risk of skin cancer

Main exposure to ionising radiation for most people is...

The natural background radiation from radon which seeps from earth's crust

Some occupations are associated with development of tumours due to exposure to carcinogens...

For example...

In construction occupations - there is increased exposure to carcinogens such as Asbestos.

Carcinogenesis stages

1. Initiation

2. Promotion

3. Progression

There is usually a long interval between the exposure to a carcinogen and clinically-detectable neoplasia. This period is called the ___ period

There is usually a long interval between the exposure to a carcinogen and clinically-detectable neoplasia. This period is called the latency period

Pre-malignant (benign) tumours that can progress to invasive, malignant carcinomas

Papilloma

Animal tests have shown that chemical carcinogens, called ___, must be given first, followed by a second class of carcinogens called ___

Animal tests have shown that chemical carcinogens, called initiators, must be given first, followed by a second class of carcinogens called promoters

The cell cycle

The regular sequence of growth and division that cells undergo

Some infections directly affect genes which control cell growth. They are carcinogenic.

An example of a directly carcinogenic infection is...

Human Papilloma virus (HPV) is strongly linked to cervical carcinoma

Why is HPV infection an example of a direct carcinogen?

HPV infection is an example of a direct carcinogen becuase it expresses E6 and E7 proteins which inhibit p53 and pRB protein function respectively (both of which are important for cell proliferation).

Some infections indirectly affect genes which control cell growth.

An example of a indirectly carcinogenic infection is...

Hepatitis B and Hepatitic C viruses are indirect carcinogens that cause chronic liver injury and regeneration

Bacteria and parasites can also indirectly lead to neoplasms.

Give an example of a bacteria that acts as an indirect carcinogen

Helicobacter pylori causes chronic gastric inflammation

Bacteria and parasites can also indirectly lead to neoplasms.

Give an example of a parasite that acts as an indirect carcinogen

Parasitic flukes cause inflammation in bile ducts and bladder mucosa = increases the risk of cholangiocarcinoma and bladder carcinomas respectively.

BViruses can also indirectly lead to neoplasms.

Give an example of a virus that acts as an indirect carcinogen

HIV acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur such as human herpes 6 virus and Kaposi's sarcoma

Knudson's two-hit hypothesis

Both copies have to be defective in same cell to allow tumor to develop

In the case of familial cancers such as retinoblastoma (malignant retinal tumour), Knudson's two-hit hypothesis states that...

1) First hit is delivered via germline and affects all cells of the body (via germline)

2) Second hit is somatic (any cell other than an undifferentiated stem cell or gamete) mutation

An example of an inherited predisposition to neoplasia

Retinoblastoma

Dominant pattern of inheritance

Knudson (1971) proposed that retinoblastoma was caused by TWO mutational events

In the dominantly inherited form of the disease, one mutation is inherited via the germ-line and the second occurs in somatic cells.

In the nonhereditary form, both mutations occur in somatic cells.

Mechanism of retinoblastoma

Loss of retinoblastoma protein (RB) in the prototypic tumour suppressor gene

If a child inherits one dysfunctional copy of the RB1 gene, half of their retinoblastoma protein is functional and half is dysfunctional.

Sufficient RB1 protein can be produced from just ONE copy of the RB1 gene to allow for normal function as RB1 is ___

Sufficient RB1 protein can be produced from just ONE copy of the RB1 gene to allow for normal function as RB1 is DOMINANT

Mutations in ___ or ___ have been associated with familial breast cancer

Mutations in BRCA1 or BRCA2 have been associated with familial breast cancer

Mutations occur in either the BRCA1 or BRCA2 which encode the BRCA1 and BRCA2 tumour suppressor proteins which are involved in repairing DNA double-strand breaks.

Mutations in BRCA1/2 are also associated with other cancer types, such as...

Ovarian cancer

Prostate cancer

Pancreatic cancer

Xeroderma Pigmentosum (XP)

Autosomal recessive = extreme photosensitivity

- Mutations in 1/7 genes that affect DNA nucleotide excision repair (NER)

- Patients develop skin cancer at a young age

Hereditary Non-polyposis Colon Cancer (HNPCC) syndrome

Autosomal dominant

- Associated with colon carcinoma and germ-line mutation affects one of several DNA mismatch repair genes

Several medical conditions are associated with an increased risk of cancer.

Give some examples...

ulcerative colitis
liver cirrhosis
hashimoto’s thyroidosis
chronic atrophic gastritis

The first human oncogene to be discovered was...

RAS

RAS proto-oncogene encodes a small G protein that relays signals into the cell that eventually pushes the cell past the cell cycle restriction point

Mutant RAS encodes a protein that is ALWAYS active - producing a constant signal to pass through the cell cycle's restriction point

Inactivation of both RB alleles allows unrestrained passage through the restriction point.

One component of growth control (the restriction point) can be deregulated either by an activated oncogene or by an inactivated tumour suppressor (TS) gene.

This idea can be extended to other master regulators of growth and respective proto-oncogenes and tumour suppressor genes that affect them.

Proto-oncogenes can encode...

Growth factors e.g., PDGF

Growth factor receptors e.g., HER2

Plasma membrane signal transducers e.g., RAS

Intracellular kinases e.g., BRAF

Transcription factors e.g., MYC

Cell cycle regulators e.g., CYCLIN D1

Apoptosis regulators e.g., BCL2

Some infectious agents can cause cancer indirectly and directly.

Name some infectious agents and the cancer site associated with them

Which HPV strains are strongly associated with cervical carcinoma?

HPV-16

HPV-18

These DNA virus strains are strongly associated with cervical cancer

HPV-16 and HPV-18 express the viral oncogenes = ___ and ___ (strong association with cervical cancer).

Integration of HPV DNA into the host genome allows the transcription of two oncoproteins (___ and ___).

HPV-16 and HPV-18 express the viral oncogenes = E6 and E7 (strong association with cervical cancer).

Integration of HPV DNA into the host genome allows the transcription of two oncoproteins (E6 and E7).

E6 viral protein (HPV) inhibits human ___ function while E7 viral protein inhibits human ___ protein function

E6 viral protein (HPV) inhibits human TP53 function while E7 viral protein inhibits human RB1 (pRB) protein function

Explain the role of (proto)oncogenes (which encode (proto)oncoproteins) (notably RAS, MYC and HER2), tumour suppressor (TS) genes (which encode TS proteins) (e.g. pRB and p53) and caretaker genes (which encode various DNA-repair proteins), in neoplasia

Proto-oncogenes encode a range of proteins with a range of normal functions e.g., growth factor (e.g. PDGF).

Tumor suppressor proteins (TSPs) are the breaks e.g., the tumour suppressor transcription factor tumour protein 53 (TP53) regulates the expression of downstream proteins that act to stop the cell-cycle to facilitate DNA repair and/or induce apoptosis.

When they have a function-altering mutation, proto-oncogenes can become oncoproteins (jammed accelerator pedals).

Conversely, when TSPs don't work, they effectively become 'broken break pedals'.

___ and inactivated ___ can act synergistically to promote cancer cell growth

Oncoproteins and inactivated TSPs can act synergistically to promote cancer cell growth

This illustrates how one component of growth control, the restriction point, can be deregulated either by oncogenic mutations in the RAS protooncogene to yield the RAS oncoprotein or by an inactivated TSP (tumour suppressor protein) RB.

Give examples of the tumour-suppressor proteins (gatekeeper proteins)

RP and TP53 are gatekeeper proteins

- TP53 is a transcription factor that is involved in regulating the expression of several pro-apoptotic proteins (guardian of the genome).

- TP53 is mutated in >50% of cancers

Give examples of the caretaker proteins involved in DNA repair and maintaining genomic integrity

Caretaker proteins e.g., BRCA1 and BRCA2 and XP proteins are involved in DNA repair and maintaining genomic integrity

Most malignant tumours require MULTIPLE alterations affecting combination of multiple TS genes and proto-oncogenes.

Give an example of this.

Colonic carcinoma - which usually begins as colonic adenoma from which arises a carcinoma.

This is known as the adenoma-carcinoma sequence.

This illustrates the stepwise accumulation of mutations in malignant neoplasms.

Cancer progression

The stepwise accumulation of mutations is called cancer progression.

Cancer evolves by initiation and promotion and finally, by progression.

The exact number of mutations needed for a fully evolved malignant neoplasm is unknown but it is thought to be around...

10 or less

Fully evolved malignant neoplasms exhibit eight hallmarks of cancer plus two enabling features.

What are these hallmarks?

1) Self sufficiency in growth signals

2) Resistant to stop

3) Cell immortalisation

4) Angiogenesis

5) Resistance to apoptosis

6) Ability to produce metastases

7) Deregulated metabolism

8) Evading immune system

Two enabling features...

1) Genomic instability

2) Tumour-promoting inflammation

The cells of malignant tumours typically express several dysfunctional ___ ___ proteins and several ___.

The cells of malignant tumours typically express several dysfunctional tumour suppressor proteins and several oncoproteins.

Abnormal chromosome segregation during mitosis, chromosomal rearrangements and aneuploidy are also common in malignant cells.

Together, these alterations account for accelerated mutation rate found in malignant neoplasms known as genome instability.

Concerning DNA and Carcinogenesis there is an increased incidence of tumours if DNA repair mechanisms are deficient

Answer true or false

True

Concerning DNA and carcinogenesis point mutation is a possible cause of proto-oncogene activation

Answer true or false

True

Concerning DNA and Carcinogenesis proto-oncogene mutations are deactivating and tumour suppressor gene mutations are activating

Answer true or false

True

Concerning DNA and Carconogenesis the oncogenes most frequently involved in human cancer belong to the ras family

Answer true or false

True

Concerning DNA and Carcinogenesis a frame-shift mutation is likely to lead to loss of tumour suppressor gene expression

Answer true or false

True

Most viruses causing human tumours are RNA viruses

Answer true or false

True

HPV is implicated in anal and penile cancers

Answer true or false

True

DNA viruses replicate using reverse transcriptase

Answer true or false

False

EBV can cause nasopharyngeal carcinoma

Answer true or false

True

Kaposi’s sarcoma is caused by infection with HHV8

Answer true or false

True

Patients with familial adenomatous polyposis have a higher than average risk of developing cancer

Answer true or false

True

Patients with familial Paget’s disease of bone have a higher than average risk of developing cancer

Answer true or false

True

Patients with acute pyelonephritis have a higher than average risk of developing cancer

Answer true or false

False

Patients with ischaemic heart disease have a higher than average risk of developing cancer

Answer true or false

False

Patients with schistosomiasis of the bladder have a higher than average risk of developing cancer

Answer true or false

True

There is a known association between hepatocellular carcinoma and hepatitis B

Answer true or false

True

There is a known association between chondrosarcoma and rous sarcoma virus

Answer true or false

False

There is a known association between carcinoma of the cervix and human papilloma virus

Answer true or false

True

There is a known association between small cell carcinoma of lung and epstein barr virus

Answer true or false

False

There is a known association between multiple myeloma and HIV

Answer true or false

False

Stages of carcinogenesis

1) Initiation

Irreversible genetic mutation occurs in stem cell/progenitor cell

2) Promotion

Clonal expansion of initiated cells within generalised hyperplasia

Outgrowth of pre-malignant tumours = papillomas

3) Progression

Malignant conversion to an invasive carcinoma