Cancer Biology -BCH4024 Dr. Douma

3 Stages of Cancer - Primary

Benign = grows rapidly, stays within confines of tissue.

Invasive = ability to break through normal barriers between tissues

Metastatic = capacity to travel through lymphatic / bloodstream and colonize new sites in body, can generate secondary tumors which are identical to primary.

Angiogenesis

Blood vessel formation, secrete angiogenic growth factors, provides nutrients from bloodstream to growing cancer cells.

Apoptosis

Programmed cell death triggered with DNA damage, cancer typically stops this process from occurring.

Cancer Incidence increases due to

Age, environment, epigenetics, exposure to carcinogens or radiation, mutations.

Cells with more turnover = higher risk (skin, epithelial)

Cells with no replication = no risk (heart muscle, neurons)

Gas Pedal

Proto-Oncogenes = normal cellular gene, encodes protein for cell growth

Oncogene = Activated mutated proto-oncogene, leads to tumor formation, genetically dominant.

Break

Tumor Suppressor Genes = Inhibit cell division by regulation.

• Mutations such as loss of function favor excessive growth.

  • Mutations genetically recessive

3 Types of Activation Mutations for Proto-Oncogene → Oncogene

Mutation in coding sequence yielding hyperactive protein (catalytic activity)

Amplification of gene to increase its copy number, resulting in overexpression of protein (10 copies instead of 2)

Chromosome rearrangement resulting in overexpression of normal protein, could be due to being rearranged right next to an enhancer.

RAS Oncogene

G12C (Glycine 12 → Cysteine) most common mutation.

RAS cannot hydrolyze GTP, no GTPase activity.

Permanently activated RAS = signaling cascade of pro-growth factors always on

Inhibitor = K-RAS inhibitor, only targets mutated RAS with C12, increases survival outcomes.

HER2

Receptor Tyrosine Kinase (RTK) that activates RAS Pathway.

Due to amplification, replication error yields multiple usages of origin site, too many copies of HER2 gene made, results in overexpression.

Few to many hundreds of copies of a gene.

• Within a chromosome = homogenous staining region

• Extrachromosomal = double minute chromosome (cut off but not degraded)

HER2 Specifics / Treatment

HER2 RTK on plasma membrane, dimerizes with itself and binds to ligand to active RAS pathway.

HER2 related cancer = HER2+

HER2+ means so high concentration of HER2 that it dimerizes alot when not supposed to, activates RAS overly and leads to cancer formation.

Treatment = Herceptin (Synthetic antibody). This treatment binds to HER2, locking it in a monomer and preventing dimerization ~ preventing RAS pathway.

• Immune system recognizes synthetic as foreign body, kills herceptin along with binded HER2.

  • Very high survival rates with treatment, but expensive.

Aneuploidy + Types (Numerical 2 + Structural 4)

Abnormal # of chromosomes

Can have gains / losses in number of chromosomes including pairs or individual.

Structural:

• Deletions = part of chromosome deleted, no genes there.

• Amplifications = Extra length on chromosome, extra genes = amplication/overexpression.

• Inversion = part of chromosome inverted/flipped. Segment within chromosome inverted.

• Translocations = part from 2 chromosomes swap.

Medulloblastoma - Various but focus on main 2

Overexpression of GFI1B transcription factor (activates pro-growth genes) due to chromosomal rearrangements.

Inversion: segment of gene with GFI1B inverted, now next to strong enhancer.

Deletion: gene sequence (336bp) between GFI1B and enhancer deleted, next to strong enhancer.

Strong enhancer results in overexpression of GFI1B = too much pro-growth genes = Cancer.

Philadelphia Chromosome (Problem + Treatment)

Translocation. Philadelphia Chromosome = 9 + 22 close, swap genetic info.

ABL and BCR are combined, BCR-ABL fusion protein exons are formed, hyperactive kinase which activates pro-growth factors.

GleeveC inhibits this binds to ABL site, great survival rate.