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Biochemistry Y1S1 > Molecular basis of cancer > Flashcards

Molecular basis of cancer Flashcards

1
Q

What is cancer?

A

A group of diseases characterized by uncontrolled growth and continuous multiplying, may grow into adjacent tissue or spread to distant parts of the body

  • Consists of more than 100 different diseases
  • The mass of cancer cells eventually become large enough to produce lumps, masses, or tumors that can be detected
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2
Q

What is meant by no contact inhibition?

A

Contact inhibition is a regulatory mechanism that keeps the cell growing in one layer (monolayer), This feature is not available in cancer cells

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3
Q

What are the characteristics of cancer cells?

A

1) They proliferate rapidly without the need of growth signals resisting inhibitory growth signals

2) Invade local tissues and spread (death of the patients)

3) Self sufficient in growth signals

4) Insensitive to death signals, Do not become senescent 🡺 Immortalized

5) Stimulate local angiogenesis

6) Evade (escape) apoptosis

7) Evade immune system

8) Genomic instability: they acquire many mutations

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4
Q

What is the meaning of metastasis?

A

Invading of tissues

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5
Q

What converts a normal cell into a cancerous cell?

A

Genomic instability

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6
Q

What causes carcinogenesis?

A

non-lethal genetic damage

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7
Q

Mutations in which genes cause tumor development?

A

1) Oncogenes and proto-oncogene (regulates cancer cells)
2) Tumor suppressor gene (regulates cancer cells)
3) DNA repair genes

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8
Q

How can cancer develop?

A

When carcinogenesis develops in:

1) Oncogene and Proto-oncogene
2) Tumor suppressor gene
3) Genes involved in DNA repair

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9
Q

What are the oncogenes?

A

They are a mutated form of cellular proto-oncogenes, coding for oncoproteins, whose product acts in a dominant manner to accelerate cell growth/division

  • Proto-oncogenes: are genes that code for cellular proteins that regulate normal cell growth and differentiation like growth factors. The term “proto-oncogene” refers to a normal protein that has not been mutated, if exposed to certain substances it might lead to carcinogenic damage changing it into an oncogene
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10
Q

What are the functions of tumor suppressor genes?

A
  • Normal genes which produces proteins that:
    1) slows down cell division
    2) Repair DNA mistakes
    3) Tells a cell when to die (apoptosis)
  • When they do not work properly the cell can out-grow leading to cancer
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11
Q

What is the type of mutation in tumor suppressor genes?

A

Recessive mutation

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12
Q

What is the type of mutation that occurs in oncogenes?

A

Dominant mutation

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13
Q

What are the causes of cancer?

A

Genetic damage:

1) Acquired
- Chemical
- Microbes
- Radiation
- Spontaneous mutation

2) Inherited
- Autosomal dominant
- Autosomal recessive

  • Epigenetics, the change of DNA due the processes like methylation, acetylation, phosphorylation, etc
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14
Q

What is the role of epigenetics in gene transcription, and how might they lead to cancer?

A

1) DNA methylation: catalyzed by DNA methyltransferases (DNMTs) at the cytosine bases that are adjacent to guanine nucleotide (CpG “this part regulates gene expression”), repressing gene transcription (if this occurs in tumor suppressor genes, center occurring will be of high probability, cancer can occur if this happens to tumor suppressor genes

2) Histone Acetylation: Acetyl group attaches to positively charged lysines in histone tail, loosening the chromatin structure promoting the initiation of transcription, catalysed by histone acetyltransferase (HATs), if it occurs on the oncogenes it can cause cancer

CpG Methylation Makes DNA go Muted, while Histone Acetylation makes DNA Active

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15
Q

What are the heredity causes of cancer?

A

1) Familial adenomatous polyposis (colon cancer)

2) Xeroderma Pigmentosa

3) BRCA 1 & 2 mutations (breast cancer)

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16
Q

Describe familial adenomatous polyposis (colon cancer)

A
  • Rare AUTOSOMAL DOMINANT inherited cancer-predisposition syndrome
  • Characterized by hundreds-thousands of precancerous colorectal polyps, that might develop colon/rectum cancer
  • FAP is caused by a mutation in the APC gene (code for APC protein, which plays a critical role in several cellular processes and it acts as a tumor suppressor)
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17
Q

Describe Xeroderma pigmentosa?

A
  • Rare Skin AUTOSOMAL RECESSIVE disorder characterized by severe pigmentation and skin sensitivity to UV, due to the deficient repair of DNA damage by UV-light
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18
Q

Describe the cancer caused by BRCA 1 & 2 (breast cancer)

A
  • BRCA (BReast CAncer gene 1&2), AUTOSOMAL DOMINANT
  • BRCA genes are genes that help to produce helpful damaged DNA-repairing proteins (BRCA1 and BRCA2 gene products are tumor suppressors)
  • Harmful/pathogenic variation(not necessarily cause harm, but their accumulation can lead to the development of cancer) /mutation of these genes can develop cancer, and people who inherit its tend to develop cancer at a younger age
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19
Q

How can cancer be acquired?

A

Mostly results from the exposure of the cell to harmful external stimuli that cause DNA damage, which eventually leads to cancer

1) Chemical & physical damage

20
Q

Describe the chemical and physical damages that happen In the DNA, leading to cancer

A
  • Attacks O2 and Nitrogen atoms within DNA (like dimethylnitrosamine), Produced from nitrites used as food preservatives
  • Nitrites are converted into Dimethylnitosamine, which methylates guanine causing them to pair with thymine, leading to mutations in the next generation
21
Q

List some examples of carcinogens

A

1) Dimethyl-nitrosamine
2) Radiation (UV, X-ray, gamma rays, nuclear radiation)

22
Q

How can radiation induce cancer?

A
  • Causes thymine dimers (links thymines together)
  • Can pass to the next generation if not fixed (Skin cancer “UV has a strong relation with skin cancer”)
  • X-rays and NUclear radiation can cause chromosomal breakage, translocation, mutation, and genomic instability
  • X-rays and gamma rays can cause the formation of ROS
23
Q

How can viruses and bacteria induce cancer?

A
24
Q

What are some of the examples of oncogenic microbes?

A
  • Viruses can spread (integrate) their DNA into the host, affecting healthy cells’ makeup (like bacteriophage virus), causing them to turn into cancer

There are two types:

1) Acute transforming viruses: contain viral oncogenes that cause cancer

  • Human papillomavirus: Cervical cancer
  • Epstein Barr virus (EBV): Lymphoma & nasopharyngeal carcinoma
  • Hepatitis B virus: Liver cancer
  • Helicobacter pylori (bacteria): Gastric cancer

2) Slow transforming viruses: causes insertional mutations that are not specific to oncogenes, with a long tumor latency

25
Q

What are some of the microbes that have oncogenes?

A
  • Human papillomavirus: Cervical cancer
  • Epstein Barr virus (EBV): Lymphoma & nasopharyngeal carcinoma
  • Hepatitis B virus: Liver cancer
  • Helicobacter pylori (bacteria): Gastric cancer
26
Q

Define and describe the process of carcinogenesis

A
  • The process of tumor cells’ appearance (loss of control over the growth and development of normal cells), initiated by non-lethal genetic damage

1) Initiation: irreversible genetic mutation in stem cells/progenitor cells, can arise spontaneously or be induced by a carcinogen

2) Promotion: clonal expansion of initiated cells within generalized hyperplasia & outgrowth of pre-malignant tumors = papillomas

3) Progression: malignant conversion to invasive carcinoma

4) Metastasis

  • A single mutation in DNA cannot cause cancer; there must be different types, scales, and locations of mutations for cancer to occur
27
Q

Mutation in which genes result in the development of cancer?

A

1) Oncogene
2) Tumor suppressor gene
3) Genes involved in DNA repair

28
Q

What is the difference between oncogenes and tumor suppressor genes?

A

1) Uncontrolled turning on of the proto-oncogenes form oncogenes activation🡺 cancer

2) tumor suppressor genes cause cancer when they are inactivated (turned off)

29
Q

What are the types of proteins encoded by proto-oncogene?

A

1) Growth Factors (mutations here can lead to a change in the amount/activity of GF increasing cell division)
2) Growth Factor Receptors (mutation here can make the cell active in the absence of GF “more common”)
- GFs + GF-Rs: start an “ON” signal for the cell to divide
3) Signal Transduction Proteins(RAS0AS)
4) Nuclear Regulatory Proteins (Transcriptional factors)
5) Cell Cycle Regulators
6) Regulators of apoptosis

  • All proteins involved in signal transduction are proto-oncogenes
30
Q

Describe the GF receptor mechanism of action

A

Growth factor receptors are tyrosine kinase-activated enzymatic receptors. When the external part of this receptor binds to a growth factor, it activates the internal tyrosine kinase, causing the phosphorylation of tyrosine and tyrosine residues to begin the process

  • Sometimes the mechanism by which we eliminate/hydrolyze this growth factor is inhibited, increasing the availability and half-life of the growth factor, allowing it to continue binding to and activating receptors and increasing cellular growth.
31
Q

How are oncogenes activated?

A

1) Signal transduction proteins (like RAS “monomeric small G protein”):
- Activated directly/Indirectly via growth factor receptors
- Their activation triggers a phosphorylation cascade, resulting in changes in the gene expression
- RAS activates mitogen-activated kinase pathway which is responsible for the promotion of cellular responses like proliferation where it will be locked when mutated

2) Promoter Insertion (like Myc gene): which is responsible for normal cell proliferation, increasing their amount in normal cells which can increase the proliferation rate substantially

  • Like in Burkitt’s lymphoma, where there is an abnormal translocation moving chromosome 8 to 14, resulting in the translocation of the myc gene under the promoter heavy chain (Vh)
32
Q

What are the transcriptional factors and what is their role?

A
  • Example includes: Myc, Fos & AP-1

They are proteins that control/regulate the rate of genetic information transcription from DNA to RNA

They control the genes by binding to specific DNA sequence domains called “promoter sequences”, those genes are responsible for the process in the cell cycle

33
Q

How does the oncogenes affect the cell cycle?

A

The cell cycle is activated by Growth factors, hormones, and other activators, and they are regulated by Cyclins, cyclin-dependant kinases (CDKs), and cyclin-dependant kinase inhibitor.

They can act on the cell cycle via their mutation to the tumor suppressor genes (normally suppresses cell growth and division, like P53 “genome guardian”, and Rb “Retinoblastoma protein “Gate keeper”), but both alleles in the gene must be mutated while in oncogenes only a mutation in one of the alleles is enough

34
Q

What are the function of the different cell cycle checkpoints?

A

1) G1 checkpoint:
- Cell has reached a large size to divide and whether there is any damage to the DNA

2) G2/M checkpoint:
- Ensures that all DNA has been replicated

3) M checkpoint:
- Ensures that the sister chromatids are attached to the mitotic spindle

35
Q

What is the function of P53 “Genome guardian”?

A
  • It is a transcriptional activator

1) DNA Damage = Increase in P53 conc
2) Increases the expression of P21 (cell cycle inhibitor, promotes both CDK/cyclin inhibition and cell cycle arrest during the G1/S phase)
3a) Repairs the DNA, permitting the cell to move further into S-phase and continue its synthesis
3b) If the DNA damage is too excessive, p53 triggers cell death by apoptosis

36
Q

What is the function of Retinoblastoma (RB) “Gatekeeper”?

A

It is a tumor suppressor protein, preventing excessive cell growth via its inhibition of E2F (epidermal growth factor) until the cell is ready to divide which then it will be phosphorylated to become inactive (via CDK)
- Mutations to pRB will cause excessive proliferation (increase E2F) thus cancer
- It is a major G1 checkpoint, blocking the cell’s entry into the S-phase

37
Q

Smoking increases the risk of which types of cancer?

A

1) Lung
2) Pancreatic
3) Bladder

38
Q

What are the hallmarks of cancer?

A

1) In-sensitivity to antigrowth factors

2) Tissue invasion and metastasis

3) Limitless replication

4) Sustained angiogenesis

5) Evading of apoptosis

6) Self-sufficiency in growth signals

39
Q

What is meant by self-sufficiency in growth factors?

A

Normal growth factors include:
- Epidermal growth factor
- Fibroblast growth factor
- Platelet-derived growth factor

Cancer cells can acquire the ability to synthesize and secrete their own growth factors independently without external signals by:
1) Altering the extracellular signaling (EGFR Overexpression)
2) Altering the transcellular transducers of specific receptors (EGFR mutation)
3) Altering intracellular circuits (RAS mutation & B-RAF mutation)

40
Q

What is meant by insensitivity to anti-growth signals?

A

Making the cell unresponsive to the G1 phase of the cycle, evading negative regulation. They do that by mutation to the Rb & p53 tumor suppressors making the cell insensitive to anti-growth factors like:

  • E7 protein, from HPV, binds to the Rb protein preventing it from binding to the host transcription factor E2F; developing cervical cancer.
41
Q

What are the evasion strategies that cancer cells use?

A
  • They evade apoptosis (which is down in response to the breakdown of enzymatic proteins called “Caspases”)

Cancer cells can:

1) modulate apoptotic pathways transcriptionally, translationally, and post-translationally.

2) Increases the expression of anti-apoptotic genes/stabilizing the anti-apoptotic genes (like BCL-2)

3) Decreases the expression of pro-apoptotic genes, and destabilizes their proteins

4) Gets rid of P53 The master of apoptosis

5) Gets rid of Caspase-3 protein expression (causes prostate cancer)

42
Q

What is meant by limitless replication potential?

A

Telomeres are located at the end of the chromosomes and regulate the cell cycle and life, as they become shorter with each division. In cancer, the cell acquires high levels of constitutively expressed enzymes permitting further proliferation of the cell

43
Q

What is meant by invasion and metastasis?

A

1) Metastasis: E-cadherins are essential for cell-cell attachment, In cancer cells E-cadherins gene undergoes deletion/mutational inactivation causing detachment via reducing the expression of cell adhesion molecules (CAMs), and E-cadherins

2) Invasion: Tumor cells invade the extracellular tissue by the release of proteinase into the ECM degrading the protein in the basement membrane

44
Q

What is meant by intravasation?

A

The access of tumor cells to the blood/lymphatic circulation

45
Q

What is meant by Extravasation?

A

Binding of tumor cells into the vascular wall via vascular cell adhesion molecule 1

46
Q

What is meant by sustained angiogenesis?

A

Angiogenesis (formation of new blood vessels) is required by the tumor for their survival, Mediated by:

1) Hypoxia, which induced Hypoxia-induced factor (HIF-1) that increases vascular endothelial growth factor (VEGF) levels, that binds to VEGF receptors causing the proliferation of the endothelial and formation of new BV

  • Other factors that stimulate the growth of angiogenesis are fibroblast growth factor and angiopoietin
47
Q

What is meant by tumor heterogeneity?

A

There are two types:

1) Temporal heterogeneity: variation in the type or organization of malignant genes across time

2) Spatial heterogeneity: How different geographic areas have different malignant gene types/arrangement

Biochemistry Y1S1 (6 decks)

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