VIII Curso Internacional del PIRRECV. Some molecular mechanisms of cancer

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1 VIII Curso Internacional del PIRRECV Some molecular mechanisms of cancer Laboratorio de Comunicaciones Celulares, Centro FONDAP Estudios Moleculares de la Celula (CEMC), ICBM, Facultad de Medicina, Universidad de Chile A.F.G. Quest,

2 Deaths in Chile, 1970, 1990, 2004

3 Prevalence of different types of cancer in Chile Organ/ranking female male 1 st 2 nd 3 rd 6th 7th 11th 10th

4 MODEL OF COLON CANCER Normal Tissue Polyps & Adenomas Adenocarcinoma

5 Normal Colon Colorectal Cancer Cell Death Proliferatión Apoptosis Apoptosis Proliferation Apoptosis Proliferation Normal Cancer Normal

6 COLON CANCER Polyps & Adenomas Infiltration of ganglia Adenocarcinoma Metastasis E-cadherin

7 What happens when cancer develops? Molecular changes In cancer, cellular communication is altered. For example: 1. Loss of contact inhibition 2. Increased sensitivity to growth factors 3. Reduced cell death

8 Acquired capabilities of cancer cells

9 Some signalling elements relevant to cancer

10 Parallel pathways of tumorigenesis

11 Some signalling elements relevant to cancer

12 Oncogenes & Tumor suppressors

13 What are oncogenes? The genetic mechanisms of transformation were discovered through the actions of transforming viruses, in which the transforming effect could be mapped to specific oncogenes. DNA viruses express proteins analogous to key proliferation factors; e.g. adenovirus E1A or SV40 large T The oncogenes of RNA retroviruses are not merely substitutes, but are derived from critical cellular regulatory genes with gain of function mutations (c-src or v-src) Evidence suggests that cancer actually develops from within, rather than via infection, by accrual of genetic changes affecting cell regulation Examples: Oncogene proto-oncogene function virus induced tumor abl protein tyrosine kinase mouse leukemia bcl-2 anti-apoptotic factor lymphoma erb-b EGF-receptor/tyrosine kinase chicken fibrosarcoma fos nuclear transcription factor mouse osteosarcoma jun AP-1 transcription factor chicken fibrosarcoma mos ser-thr kinase mouse sarcoma myc nuclear protein chicken myelocytoma H-ras GTP protein rat sarcoma sis platelet derived growth factor monkey sarcoma src non-receptor tyrosine kinase chicken sarcoma

14 Src Tyrosine Kinases Structural Features Membrane Attachment c-src Unique SH3 SH2 L Catalytic Negative Regulatory G2,C3,C5(6) K Y Y Membrane Attachment v-src Unique SH3 SH2 L Catalytic * **** * *** * G2,C3,C5(6) K Y (*) amino acid substitutions Modified from NRM&CB 2:467, 2001

15 The Ph Chromosome: t(9;22) Translocation Abl = Abelson tyrosine kinase Bcr = breakpoint cluster region

16 Inactive Structure of Abl cap N-lobe C-lobe

17 What are tumor suppressors? Some genes appear to be oncogenic upon loss of function, and therefore act as proliferation regulators or tumor suppressors. These include prb105 or p53, originally misclassified as oncogenes, or the more recently discovered BRCA1. Others include APC (adenomatous polyposis coli protein) These are classic examples of tumor suppressor molecules that were discovered as mutations associated with disease states. Such mutations can be either of germline (hereditary)or somatic origin. More recently, tumor suppressors are characterized based on functional properties and association of changes in expression patterns with certain disease states. An example here is Caveolin-1.

18 Cell proliferation

19 Receptor Tyrosine Kinases

20 Signaling cascade downstream of RTKs

21 Unlimited replicative potential

22 Telomers and telomerases The Hayflick limit, of some division cycles for human diploid fibroblasts, is mediated by telomere length. Telomerase is active in germline cells, but inactive in somatic cells. Cells reach senescence when the short telomeres trigger the protective mechanisms of p53, which stimulates the CKIs to halt further cell cycle progress. Cells reach crisis when telomeres are lost, exposing chromosome ends, and provoking the double strand repair mechanism to make inappropriate attempts at recombination and ligation. In some cases, immortalized cells maintain telomeres by reactivating telomerase, and maintain relatively stable chromosomes. However, a significant proportion of immortalized cells are viable in the absence of telomerase, and use a less well characterized process alternative of telomeres (ALT).

23 Cell survival & cell death

24 The major PI3-kinase signalling pathways and functions Mol.Med. Today (2000) 6: 338

25 Kang et al., PNAS

26 Two major apoptotic pathways in mammalian cells

27 Appearance of Phosphatidylserine on the Surface of Apoptotic Cells

28 Ingestion of apoptotic bodies by a macrophage

29 Angiogenesis

30 Angiogenesis

31 O 2 -dependent modulation of HIF activity

32 Receptor Tyrosine Kinases: VEGF The VEGF receptor is a receptor tyrosine kinase of the PDGF type!

33 Cell adhesion

34 The Integrin-Extracellular Matrix (ECM) signalling system The integrin family consists of α,β heterodimers (about 18α and 8β subunits) Transmembrane proteins with short intracellular domains. Integrate interactions between cytoplasm and ECM. Binding proteins of the ECM contain contain target RGD or related sequence (collagens, laminins, fibronectin) Also known now to interact with cell surface proteins (Thy-1)

35 Cell adhesion and survival

36 Cell-cell contact

37 Cell-cell signalling and contact inhibition: cadherins Cell-cell interactions and signalling involve proteins called cadherins (Ca dependent adhesion proteins) and intracellular effectors called catenins. Different cadherins are associated with different cell types, e.g. N-cadherin (neural), M-cadherin (mesenchyme), E-cadherin, (epithelial). Cadherins mediate self recognition by binding another identical cadherin as their extracellular ligand. Loss of E-cadherin promotes Epithelial-Mesechymal Transition (EMT)

38 Caveolin-1 as a tumor suppressor: Working model Quest lab

39 Metastasis

40 Metastasis

41 Loss of cellular adhesion Metastasis Increased invasive capacity Onset of metastasis is associated with changes in the expression of cell surface molecules: - loss of E-cadherin, which is important for cell-cell interaction - change in the expression pattern of integrins (αxβy), which are important for cell-matrix interactions - increase/change in the expression of matrix metalloproteinases (MMP9)

42 Hallmarks of tumorigenicity and cancer Disregard of signals to stop proliferating and to differentiate Autonomous generation of signals that promote growth Capacity for sustained proliferation Evasion of apoptosis Motility and invasiveness Angiogenesis.

43 Emerging and Enabling Hallmarks

44 Tumors as complex tissues