Lung Cancer Tumour Markers

The origin of cancer What is cancer? Cancer Research UK defines it as: “… when abnormal cells divide in an uncontrolled way.

The Cell Cycle

The Cell Cycle Go is modulated by: Mitogens, stimulate cell division, mostly by removing intracellular negative feedback controls that block progress through the cell cycle. Growth factors, which stimulate cell growth by promoting the synthesis of proteins and other macromolecules and by inhibiting their degradation. Survival factors, which promote cell survival by suppressing apoptosis. Resting phase or cell quiescence (heart/neuron)

ALK -1 EGFR KRAS These are tyrosine kinases The Cell Cycle Go is modulated by: ALK -1 EGFR KRAS These are tyrosine kinases

Al Pacino says: Most receptors for growth factors are tyrosine kinases Regulation of The Cell Cycle Most receptors for growth factors are tyrosine kinases A tyrosine kinase? WHAT THE &%$* IS A TYROSINE KINASE ?! Al Pacino says:

Most receptors for growth factors are tyrosine kinases Regulation of The Cell Cycle Most receptors for growth factors are tyrosine kinases Discovered in 1982 Receptor for epidermal growth factor (EGF) When activated, transfers a phosphate group from ATP to selected intracellular tyrosine side chains. These phosphorylated domains are recognised by intracellular proteins and start a signal cascade. Phase 1: Extracellular signal Phase 2: Intracellular signal cascade Phase 3: Profit.

EGFR: Epidermal Growth Factor Receptor Involved in growth; cell proliferation; differentiation and survival Family of four tyrosine kinase receptors HER-1 (ErbB-1) HER-2/neu (ErbB-2) HER-3 (ErbB-3) HER-4 (ErbB-4)

EGFR: Epidermal Growth Factor Receptor A transmembrane cell signalling receptor with four distinct domains: Tyr EGF binding site Plasma membrane Tyrosine kinase Cytoplasmic tail

EGFR: Epidermal Growth Factor Receptor How does it function? EGF EGF Tyr Epidermal growth factor (EGF) binds to its receptor (EGFR) on the cell membrane

EGFR: Epidermal Growth Factor Receptor How does it function? Homo- and hetero-dimerization of the transmembrane region and autophosphorylation of tyrosine kinase molecules. Signal cascade pathway activated (e.g.MAPK) leading to DNA synthesis and cell replication Tyr EGF P ATP ADP

EGFR: Epidermal Growth Factor Receptor RAS GDP MYC Transcription Grb RAS GTP RAS GTP SOS MEK RAF MNK CREB MAPKKK ATP ADP ATP ADP MAPKK MAPK

All this preparation is ignored Kirsten rat sarcoma viral oncogene homolog KRAS = Kirsten rat sarcoma viral oncogene homolog KRAS is a molecular switch. KRAS recruits and activates the proteins required in growth factor receptors, e.g.: B-RAF (a member of the MAPK pathway) All this preparation is ignored BRAF initiates the whole signalling cascade at this point Also known to play a role in the Warburg effect of malignant tumours. BRAF was here..

ALK-1: Anaplastic lymphoma kinase Adenocarcinoma of the lung responsible for 3-5% of non-small cell lung cancer ALK-1 is: the result of a inversion fusion gene mutation on 2q ALK and EML1 change position ALK fuses to EML4 Produces a chimeric fusion protein with constitutive ALK1 action. Promotes and maintains malignant behaviour. Almost mutually exclusive with EGFR or KRAS

TYROSINE KINASE TAKE HOME MESSAGE Cell signalling is a complicated process involving many interlocking parts One solitary change can upset the whole cascade. Molecular biology is never as simple as it appears!