Molecular and Cellular Concepts of Oncology

Question 1

Metastasis

Answer 1

Involves malignant cells break away, attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), escape, and establish secondary tumors

As long as it is not invading its surrounding normal tissues, the tumor is still considered as benign. Angiogenesis is the formation of new blood vessels in and around tumor. The purpose of angiogenesis is for tumor to obtain more nutrients for faster growth and proliferation.

Question 2

Leukemias, Lymphomas/Myelomas, CNS Cancers

Answer 2

Leukemias: cancers of hemopoietic cells

Lymphomas and myelomas - cancers that arise in the immune system

Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord

Question 3

Key Info from Genomic Studies

Answer 3

Multiple genetic mutations are needed for cancer to develop

Different cancer requires (contains) different number of genetic(gene) mutations

Skin cancer and lung cancer contain the most genetic mutations

Mutations in both tumor suppressor genes and proto-oncogenes are needed for cancer to develop

Question 4

Driver vs. Rider Genes of Oncogenesis

Answer 4

Certain gene mutation(s) at a given stage of oncogenesis are the most important for oncogenesis to proceed (drivers)

Other gene mutations play very small or no roles in oncogenesis at that stage (riders)

At different oncogenesis stages, drivers may be (usually) different; riders can change into drivers and vice versa

The most effective anticancer therapies are those that target driver genes

Question 5

Genetic Development of Colorectal Cancer

Answer 5

Loss of APC tumor suppressor gene
Activation of K-ras oncogene
Loss of DCC tumor suppressor gene
Loss of p53 tumor-suppressor gene
Other changes in genes whose products are involved in assisting metastasis
Same cancer from different people may have different mutations in different sets of genes (or different sequence of mutations).

Question 6

Cancer Stem Cell Hypothesis

Answer 6

Cancer cells are fast replicating and usually less-differentiated, and immortal cells

Hypothesis: tumors often originate from the transformation of normal stem cells, similar signaling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells include ‘cancer stem cells’ — rare cells with indefinite potential for self-renewal that drive tumorigenesis

Question 7

Clonal Evolution vs. Cancer Stem Cell Model

Answer 7

Clonal: no matter the genetic make up of a cell, they can each form a new tumor

Cancer stem cell model: only the cancer stem cell can establish the new tumor

Question 8

Cancer Stem Cells (CSC)

Answer 8

Cancers have cancer stem cells that are responsible for most of the cancer growth, metastasis, and drug resistance

Different cancers have different CSC (different cell surface markers)

Different cancers have different percentage of CSC

CSC has become a new therapeutic target in cancer treatment

Question 9

Proto-Oncogenes vs. Oncogenes

Answer 9

Proto-oncogenes: Normal cellular genes that encode proteins involved in various aspects of cell growth and cell proliferation.

Oncogene: Cancer-producing genes that are derived from proto-oncogenes by various types of genetic mutations.

Proto-oncogenes and oncogenes are growth (cell proliferation) promoting genes, while tumor suppressor genes are growth-suppressing (-decelerating or -inhibiting) genes

Question 10

7 Proteins that Control Cell Growth

Answer 10

Seven types of proteins:

1. Growth factors
2. Growth factor receptors
3. Intracellular transducers
4. Transcription factors
5. Pro- or Anti-apoptosis proteins
6. Cell-cycle control proteins
7. DNA-repair proteins

Cancer result from expression of mutant forms of these proteins
Normal growth factors (proteins) become oncogenic when they are over-expressed (over-produced)

Question 11

HER2

Answer 11

Receptor Tyrosine Kinase (RTK)
Valine to Glutamine is the oncogenic mutation that makes the monomer HER2 receptor dimerize so when GF activated they must be dimerized and sends cell growth signals = breast cancer

Question 12

EGFR

Answer 12

EGF receptor is also a receptor tyrosine kinase (RTK)

Dimerization of two receptor proteins in the absence of normal EGF-related ligand via a deletion causes the oncogenic mutation = lung cancer

Question 13

Tyrosine Kinases

Answer 13

Mutated receptor tyrosine kinases and intracellular kinases are one type of key oncogenes

Manynew targeted anticancer drugs target (inhibit) membrane bound tyrosine kinases or intracellular kinases - TKIs

Question 14

Ras

Answer 14

GTP binding protein
Ras protein- most commonly mutated protein in all human cancer (30% of all cancers); Ras mutation makes the protein always active and sends cell growth signal constantly, which leads to cancer

Question 15

Transcription Factors: Fos and Myc

Answer 15

Fos and Myc are two important transcription factors. Their activities are tightly controlled in normal cells and they are not in active state for long.

However, in some cancer cells, you can find the Fos or Myc proteins are constitutively active, causing overexpression of genes involved in cell growth and lead to cancer.

Question 16

Proto-Oncogene to Oncogene

Answer 16

A proto-oncogene can become an oncogene by mutations in the regulatory sequence (promoter), in the coding sequence (in the gene), or by chromosomal translocation, or by gene amplification

Ex. If normal gene only has one copy, and then multiple copies are accidentally made = protooncogene and can become an oncogene

Question 17

Philadelphia Chromosome

Answer 17

One type of cancer caused by chromosome rearrangement is CML

The specific chromosome rearrangement is called chromosome translocation.. The chromosome translocation product is called Philadelphia chromosome, which is generated by the fusion or translocation of Ch 9 and Ch22, and the generation of a fusion gene of bcr and abl

Abl is a tyrosine kinase, the mutated bcr/able fusion protein becomes constitutively active, causing leukemia.

Question 18

Tumor Suppressor Genes

Answer 18

A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from becoming cancerous. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to become cancerous, usually in combination with other genetic changes.

Question 19

Retinoblastoma

Answer 19

They inherit one mutant allele of the RB gene. Somatic
mutation of the other allele coupled with oncogenic mutations in other genes leads to tumor development

Rb gene is a tumor suppressor gene

Question 20

Two Hit Hypothesis

Answer 20

The two-hit hypothesis – some forms of hereditary cancer might be initiated when a cell in a person heterozygous for a germline mutation undergoes a second, somatic mutation in the other allele of the same gene, thus rendering the cell homozygous for loss of function mutations in a tumor-suppressor gene and giving rise to a tumor

This theory applies only to tumor suppressor genes, not oncogenes.
It applies to the same tumor suppressor gene, not two different tumor suppressor genes

Question 21

p53

Answer 21

Tumor suppressor, transcription factor mutated or deleted in > 50% of all human cancers
**Involved in DNA damage repair, cell cycle checkpoint control, and apoptosis

Guardian of human genome”

Cause of the genetic diseases Li-Fraumeni Syndrome

Question 22

Oncogenes vs. Tumor Suppressor Gene Mutations

Answer 22

Oncogenes: cell growth promoting, but mutation causes gain of function and somatic mutations; dominant inheritance (only need one allele)

Tumor suppressor gene: cell growth suppressing, but mutation causes loss of function; must receive both alleles (recessive inheritance), but classified as dominant

Question 23

Telomeres

Answer 23

A telomere is a region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from destruction (similar to the plastic caps at the ends of shoelace).

Telomeres are shortened during cell division and replenished by telomerase (2009 Nobel Prize)

As telomeres grow shorter, eventually cells reach the limit of their replicative capacity and progress into senescence.

Question 24

Telomeres and Cancer Development

Answer 24

Telomere shortening can induce replicative senescence which blocks cell division. This mechanism prevents genomic instability and development of cancer in aged cells by limiting the number of cell divisions.

Cancer cells which bypass this arrest become immortalized by telomere extension mostly due to the activation of telomerase, the enzyme responsible for synthesis of telomeres.

Compared to normal cells, cancer cells’ telomerase activity is higher and telomeres are longer – two of key reasons that cancer cells are immortalized

Question 25

RNA and DNA Viruses as Cancer Producing Agents

Answer 25

Both RNA and DNA viruses can carry oncogenes
Both RNA and DNA viruses can induce cancer in animals and humans
Oncogenes carried by RNA viruses do not have functions in viral replication cycle, whereas oncogenes carried by DNA viruses do participate in the replication cycle of viral hosts.
Oncogenic mechanisms of the oncogenes carried by RNA viruses are very different from those of the oncogenes carried by DNA viruses

Question 26

Retroviruses

Answer 26

There are two mechanisms for retroviruses to cause cancer – fast or slow tumor-forming
The genome of fast tumor-forming retrovirus contains an oncogene (onc)

Question 27

Activation of the c-myc

Answer 27

Activation of the c-myc Proto-oncogene by Retroviral Promoter and Enhancer Insertions (slow-acting retrovirus) triggers tumorgenesis

Promoter insertion: RNA transcript promoted from right hand viral LTR
Enhancer insertions: RNA transcript promoted from cell sequences but enhanced by viral sequences

Question 28

Human Papilloma Viruses (HPV)

Answer 28

Can cause cervical cancer
Once inside the cells of their host, HPV synthesize
a protein designated E7 – an oncogene product

E7 binds to Rb, and RB is a tumor suppressor gene, so unable to suppress tumor growth and allows cancer to grow
E6 – inactivates p53 tumor suppressor gene allowing cancer to progress

Question 29

Proto-Oncogenes: RTK, Signal Transducer, and TF

Answer 29

RTK: HER2/EGFR
Signal Transducer: Ras
TF: c-fos and c-myc

Question 30

DNA vs. RNA

Answer 30

DNA: +oncogene, - tumor suppressor gene, + oncogene as part of a normal viral genome, and + oncogene has normal function in viral cycle

RNA: +/- oncogene, - tumor suppressor gene, - oncogene as part of normal viral genome, and – oncogene has normal function in viral cycle

Question 31

Checkpoints, CDKs, and Cyclins

Answer 31

Presence of checkpoints are designed for checking correctness is cell development

Cyclin levels fluctuate and CDK = both work together to progress the cycle