Carcinogenesis is a multi-step process. Here are images of different stages in the development of breast cancer. What is each stage called and characterized. What abilities do tumor cells have to acquire to progress from stage to stage. Can you name some proteins that provide these abilities?
The first image is a normal duct (with epithelial and myoepithelial cells). The second is ductal carcinoma in situ (DCIS). The third image is invasive carcinoma arising out of DCIS, and fourth is metastatic invasive carcinoma to a lymph node. Through the activation of oncogenes and the inactivation of tumor supressor genes (in italic), tumors must acquire many abilities. Pathways/proteins may also be indirectly upregulated/activated by oncogenes that affect the transcription of many proteins.
Mutagenesis (oncogenes / suppressors that promote mutation in the first place)
- DNA Repair: BRCA-1 & 2, xeroderma pigmentosum X(XP-1)
Mitogenesis (proliferation that is non-responsive to normal growth signals)
- Growth factor receptors: EGFRs (e.g. HER2/neu), c-met (HGF-R), c-kit, VEGRs
- Downstream transducers: ras, abl, raf, APC/beta-catenin, NF1 & 2, PTEN, SMADs
- Transcriptional activators: myc, WT1
Immortality (evasion of apoptosis and limitless mitosis)
- Cell-cycle regulators: cyclins, CDKs, RB1
- Checkpoint components: p53, ataxia-telangiectasia
- Anti-apoptotics: bcl-2
Invasiveness (ability to invade through basement membranes and stroma)
- Loss of adhesion: E-caderin
- Matrix degradation: metalloproteinases
- Motogenesis
- epithelial-mesenchymal transition (cadherin/catenin) via SNAIL & TWIST
- paracrine-autocrine growth loops (HGF/met)
Angiogenesis: VHL, VEGF/VEGF-R, hypoxia inducible factor
Metastasis
- Chemokine receptors: CXCR4, CCR7 (preferential metastasis to chemokine-secreting organs, "soil & seed" )
- Osteolytics (PTHRP -> osteoblasts/osteoclasts -> release of growth factors embedded in bone matrix (IGF & TGFb)
