Neoplasm

• neoplasm = tumour = collection of tumour cells plus others

• benign or malignant

• cancer = malignant neoplasm

• tumours are created when normal cell cycle control checkpoints are bypassed

  • results from genetic and epigenetic changes

  • consequences

    • chromosome instability

    • cell evade cues that inhibit growth

• benign tumours can be life-threatening

consequences of checkpoint

normal vs neoplasm

benign vs malignant

malignant neoplasm

1. sustaining proliferative signalling

2. evading growth suppressors

3. avoiding immune destructino

4. enabling replicative immortality

5. tumor-promoting inflammation

6. activating invasion and metastasis

7. inducing angiogenesis

8. genome instability and mutation

9. resisting cell death

10. deregulating cellular energetics

• these 10 are never seen in normal tissues

angiogenesis

• blood vessel formation promoted by

  • increasing angiogenic factors like VEGF

  • decreasing angiogenic inhibitors

senescence

• this occurs because telomeres get shorter with each cell division

• Hayflick limit (60-70 doublings in cultured cells

  • telomeres shorten to a critical length and activate DNA damage response

• normal cells have no telomerase

• overactive telomerase = restores telomeres, so critical length of telomeres is not reached

to avoid senescence

p53 and apoptosis

• a loss of function mutation in p53 prevents Bax accumulation, therefore no apoptosis in neoplastic cells

Tumour progression

1. initiation phase

   1. mutations occur in one or more driver genes

2. clonal expansion phase

   1. additional mutations accumulate, allowing cell proliferation

3. invasive phase

   1. additional mutations enable cells to invade normal tissue

increasing the chances of acquiring TSG and proto-oncogene mutations or becoming aneuploid is a characteristic that enables cancer

tumourigenesis

1. one key mutation can lead to accumulation

2. first mutation increases susceptibility to more mutations

3. results in clonal expansion

tumours can be genetically heterogenous

types of key genes

• p53

• Rb

• Ras family

proto-oncogenes

• proto-oncogenes become an oncogene when altered by a mutation

• normally, they perform cellular functions related to growth, proliferation or apoptosis

  • growth factors

  • receptors

  • TF

  • signaling enzymes

Ras

• in normal cells, mitogen binds to receptor tyrosine kinases which then activate Ras

  • Ras is a GTPase that acts as signal transducer

  • Ras is active when bound to GTP

• mutant cells can’t breakdown GTP

  • the result is a constant unregulated MAP kinase casecasde

  • results in increased cell proliferation

tumour suppressing genes

normal genes that are involved in

• negatively regulating cell cycle

• positively regulating apoptosis

• coupling cell cycle to DNA damage

• DNA repair genes

• cell adhesion

these genes generally follow two hit hypothesis

can be uncovered via loss of heterozygosity

2 hit hypothesis

• developed from study of RB1 and its role in retinoblastoma

• cancer development requires 2 hits

  • familial: one mutation is inherited (first hit)

    • all cells have this mutation

    • only one more mutation is required to start cancer development, this is the second hit

  • destroys wild type allele = loss of heterozygosity (LOH)

    • because of loss of normal allele when other is already abnormal

      

  • very likely that cancer results in pedigree seen for autosomal dominant disorder

    • dominant at organism level; recessive at genotype level

• sporadic cancer

  • both mutations need to occur in same cell

    • much less likely, so fewer numbers of primary tumours

p53

• tetrameric TF

• mutations prevent DNA binding

• one mutant subunit and DNA is prevented from binding

• mutations can create monomers/dimers

• dominant-negative mutation

  • even if there is functional p53 present, if there is mutated p53, it will interfere with regular p53 function

epigenetics and cancer