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Biology And Pathophysiology Of Cancer
- 1. Biology of Cancer Pathophysiology of Cancer Raul H. Morales-Borges, M.D., FICPS, FIACATH Ashford Institute of Hematology & Oncology
- 20. Carcinogenesis
- 21. Molecular abnormalities in lung cancer Commonly observed genetic changes Tobacco carcinogen Inappropriate response to external signals Loss of cell cycle control Loss of apoptosis pathway Loss of contact inhibition Ability to metastasise Angiogenesis Immortality Autocrine growth loops Atypical alveolar hyperplasia Premalignant adenomas Lung cancer Carcinoma in situ Dysplasia Bronchial metaplasia Normal epithelium
- 22. Sequential changes during lung cancer pathogenesis Early Intermediate Late Normal epithelium Hyperplasia Dysplasia CIS Invasive carcinoma ~80% 3p LOH/small telomeric deletions 3p LOH/contiguous deletions ~50% Microsatellite alterations ~70% 9p21 LOH ~80% Telomerase dysregulation Telomerase upregulation ~60% myc overexpression ~80% 8p21-23 LOH ~40% Neoangiogenesis ~40% Loss of Fhit immunostaining ~70% p53 LOH p53 mutations ~80% Aneuploidy ~100% Methylation ~30% 5q21 APC-MCC LOH ~20% K-ras mutation Hirsch et al 2001 LOH, loss of heterozygosity
- 35. Holistic scheme of multistage carcinogenesis with 3 types of control systems Agonist induced signal transduction Cell cycle control Fidelity of DNA and Chromosome replication
- 40. Model of role of angiogenesis in metastasis Angiogenesis Expansion of Tumor cells Microinvasion Enter & Exit Circulation Limited growth in Target Organ Angiogenesis Expansion into detectable metastasis
- 42. Cyclin E* Cell cycle and therapeutic targets DNA damage or oxygen deprivation Cell suicide (apoptosis) p53* p21 Inactive pRB protein External signal that inhibits cell division TGF Rb + E2F Early G 1 Late G 1 S G 2 M Phases of cell cycle p15* p16* p27 green Activity that promotes cell division pink Activity that discourages cell division * Mutation or deregulation of gene for this protein has been found in human tumours R External signal that promotes cell division Cyclin E- CDK2 complex Proteins involved in DNA synthesis CDK2 DNA synthesis Cell division Cyclin B- CDK1 complex Cyclin A CDK1 Cyclin B Cyclin A- CDK1 complex Liberated transcription factors Cyclin D- CDK4/6 complex CDK4/6 Cyclin D*
- 44. Strategies for signalling inhibition Tyrosine kinase inhibitors (TKIs) Immune effector cell Anti-ligand mAbs Bispecific Abs Anti-receptor mAbs Ligand/toxin conjugate scFv/toxin conjugates Ligand- genistein conjugates Intracellular scFvs Nucleus Antisense Inhibitors of other signalling molecules
- 45. DNA Mode of action of EGFR inhibitors Membrane Extracellular Intracellular R K R K EGFR-TKI EGFR-TKI Signalling Proliferation Cell survival (anti-apoptosis) Growth factors Chemotherapy/ radiotherapy sensitivity Angiogenesis Metastasis R, epidermal growth factor receptor EGF/TGF α Antibody
- 49. Inflammatory Conditions & Cancer Reactive Oxygen Species Increased COX2 Proliferation Release of growth factors Release of cytokines Injury Cancer
- 51. Histopathological Appearance of Benign Breast Disease (Hematoxylin and Eosin) Hartmann, L. et al. N Engl J Med 2005;353:229-237 BENIGN BREAST DISEASES (FIBROCYSTIC BREAST DISEASE)
- 63. Genomic instability & Radiation Bystander effect & Gap Junction Intercellular Communication Mitotic failure Cell death Chromosome alteration Gene mutation DNA damage Ionizing radiation
- 65. Multistep skin Carcinogenesis Protein oxidation Lipid peroxidation Xenobiotics Mutate protooncogenes Inflammation ROS Direct DNA Damage UVR Oxidative Stress
- 69. Biologic mechanisms of obesity and cancer Free fatty acids, TNF, Resistin Increased bioavailability of Insulin-like growth factor-1 Increased WEIGHT ADIPOSITY Insulin resistant Decreased liver synthesis, blood, and tissue of insulin-like growth factor binding protein 1 & 2 Decreased apoptosis & Increased Cell proliferation Tumor development
- 70. Obesity, hormones, and cancer Aromatase & 17-B-Hydroxy Steroid Dehydrogenase Diffusion into target organs Decreased apoptosis Increased Proliferation Loss of differentiation Adipose tissue Increased bioavailability of Estradiol & testosterone Reduced levels of Sex Hormone Binding Globulin
- 85. THANK YOU !!!
Notas do Editor
- Loss of heterozygosity is a molecular detection method used to indicate deletion of one allele of a tumour suppressor gene (TSG). Both copies of TSGs are usually lost or mutated in the cancer phenotype. The most frequent genetic abnormalities found in lung cancers occur in TSGs. For example, p53 is mutated in >90% of SCLC and >50% NSCLC. The retinoblastoma TSG is also mutated in >90% of SCLC but in only 15% of NSCLC. p16 is another component of the retinoblastoma pathway, which is rarely abnormal in SCLC but is inactivated in >50% NSCLC. Additional evidence has confirmed that SCLC and NSCLC differ significantly in the TSGs that are inactivated during their pathogenesis. 1 myc oncogenes are commonly overexpressed in both SCLC and NSCLC, while ras is not mutated in SCLC but is mutated in 30% of NSCLC. 1 Preneoplastic lesions have been found to contain several molecular genetic abnormalities identical to some found in invasive carcinoma. 2 These include p53 mutations and increased immunoreactivity, myc and ras upregulation, cyclin D1 overexpression, bcl-2 overexpression, allele loss at several loci (3p, 9p, 8p and 17p) and DNA aneuploidy. 2 Molecular changes detected frequently in dysplasia are regarded as intermediate changes, and those detected at the carcinoma in situ or invasive stages are regarded as late. Although there is a common order in which molecular changes occur, exceptions are found. References 1. Wistuba II, et al. Semin Oncol 2001; 28 (2 Suppl 4): 3-13. 2. Hirsch FR, et al. Clin Cancer Res 2001; 7: 5-22. Slide figure reproduced from reference 2 with permission from the American Association for Cancer Research, Inc.
- TGF , t ransforming growth factor beta (an inhibitor). R, restriction point. Once the restriction point is passed, the cell is committed to undergo cell division. A number of signalling pathways, such as the epidermal growth factor receptor (EGFR) pathway, feed into the cell cycle, which is regulated by many molecular interactions. In its active form pRB inhibits the progression from the G0/G1 to S phase of the cell cycle by sequestering E2F transcription factors. Phosphorylation of pRB liberates these transcription factors and subsequently promotes cell-cycle progression. Cell-cycle regulation at this checkpoint may be altered by other mechanisms that increase the phosphorylation of pRB (including overexpression of cyclin D or lack of expression on p16), which is then unable to inhibit progression to S phase. Overactivity of the stimulatory proteins cyclin D, cyclin E and CDK4 have been implicated in certain human cancers. Inactivation of various inhibitory proteins has also been documented, including p53, pRB, p16 and p15. The net effect of any of these changes is deregulation of the cycle and, in turn, excessive proliferation of the cell. Reference Weinberg RA. Sci Am 1996; 275: 62-70. Slide figure reproduced from reference 1 with permission.
- New prognostic markers for estimating survival outcome and monitoring treatment are helpful to select patients with poor prognosis for new therapeutic strategies. 1 A recent study has demonstrated that the presence of serum p53 antibodies is an independent prognostic factor in patients with limited-stage SCLC (p=0.033). For example, the median survival was 10 or 17 months in those with or without p53 antibodies (p=0.014). 2 Several other members of the p53-p21 pathway and the pRb pathway have been found to be altered in lung tumours. 3 Decreased expression of tissue inhibitors of matrix metalloproteinases (TIMP-1) has been correlated with response in patients with SCLC (p=0.043). 4 Increased expression of matrix metalloproteinases (MMP-3, MMP-11, and MMP-14) was also an independent negative prognostic factor for survival. 4 Chromogranin A, a protein present in neuroendocrine vesicles, has also been shown to be an important prognostic factor for survival after performance status and disease stage. 5 In addition, expression of topoisomerase II and (implicated in resistance to doxorubicin and etoposide) has been shown to be predictive of poorer survival and lower response rates, respectively. 6 A consistent association has been shown where lung cancer risk is decreased by a G to A polymorphism in the myeloperoxidase ( MPO ) gene, which is expressed in neutrophils recruited to the lung after chemical or immunological insults. 7 The G to A transition results in reduced expression of MPO RNA and several studies have reported a reduction in lung cancer risk for the A/A compared with the G/G genotype. Levels of pleiotrophin in blood samples from patients with SCLC (n=63) and NSCLC (n=22) were compared with levels in 41 healthy people. 8 Raised levels of pleiotrophin were found in 87% of SCLC samples and 63% of NSCLC samples, compared with 2.4% of samples from healthy controls. Levels of pleiotrophin appeared to increase as the disease became more advanced. References Gandara DR, et al. Lung Cancer 2001; 34: S75-S80. Zalcman G, et al. Int J Cancer 2000; 89: 81-86. Niklinski J, et al. Lung Cancer 2001; 34: S53-S58. Michael M, et al. J Clin Oncol 1999; 17: 1802-1808. Drivsholm L, et al. Br J Cancer 1999; 81: 667-671. Dinegemans AM, et al. Clin Cancer Res 1999; 5: 2048-2058. Williams JA, et al. Carcinogenesis 2001; 22: 209-214. J ä ger R, et al. Br J Cancer 2002; 86: 858-863.
- Novel agents may interfere with a range of different components of cell signalling pathways.
- EGFR is activated by the binding of a variety of ligands [eg EGF, transforming growth factor- α ( TGF α)] to the extracellular domain. This results in receptor dimerisation, leading to activation of the receptor’s tyrosine kinase and subsequent intracellular signalling. EGFR activation has been implicated in the control of cell proliferation, survival and metastasis. 1 There is increasing evidence that EGFR is expressed in a range of human tumours, including NSCLC, and high-level expression has been correlated in many cases with poor prognosis. 2,3 Inhibitors of the EGFR in clinical development include the small molecule EGFR tyrosine kinase inhibitors gefitinib and OSI-774, and the monoclonal antibody C225. 4-6 A lack of EGFR positivity has been observed in SCLC. 7 References Woodburn J. Pharmacol Ther 1999; 82: 241-250. Salomon D, et al. Crit Rev Oncol Hematol 1995; 19: 183-232. Wells A. Int J Biochem Cell Biol 1999; 31: 637-643. Baselga J, Averbuch S. Drugs 2000; 60 (Suppl 1): 33-40. Hidalgo M, et al. J Clin Oncol 2001; 19: 3267-3279. Baselga J, et al. J Clin Oncol 2000; 18: 904-914. Cerny T, et al. Br J Cancer 1986; 54: 265-269.
- To complete the Dale Carnegie Training® Evidence – Action – Benefit formula, follow the action step with the benefits to the audience. Consider their interests, needs, and preferences. Support the benefits with evidence; i.e., statistics, demonstrations, testimonials, incidents, analogies, and exhibits and you will build credibility.
- 4. Head & Neck Cancer: Nasopharyngeal Cancer and Epstein-Barr Virus Nasopharyngeal cancer has been associated with chronic infection with the Epstein-Barr virus and is endemic in regions of Northern Africa and Asia. Accordingly, the etiology of this head and neck cancer is distinct from that of other head and neck cancers, and Epstein-Barr viral proteins are detectable in the majority of nasopharyngeal tumors. The association between the development of nasopharyngeal cancers and the frequent consumption of salted fish or nitrosamines may reflect a disease mechanism relating to the activation of the viral genome.
- Key Point There are many different types of HPV; of the 15 –20 oncogenic types, HPV 16 and HPV 18 account for the majority of cervical cancers. Background Papillomaviruses such as HPV are nonenveloped, double - stranded DNA viruses. 1 More than 100 HPV types have been detected, 2 with >80 types sequenced and classified. 3 Approximately 30 – 40 types of HPV are anogenital, of which 15 –20 types are oncogenic. 2,3 HPV Types 16 and 18 are oncogenic and account for about two thirds of all cervical cancers—the next 5 most prevalent types (31, 33, 45, 52, 58) account for only an additional 18% of cases. 4 Other oncogenic HPV types include 35, 39, 51, and 56. 5 HPV Types 6 and 11 are nononcogenic and are associated with external genital warts. 3 References 1. Howley PM. Papillomavirinae : The viruses and their replication. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology . 3rd ed. Philadelphia, Pa: Lippincott - Raven; 1996:2045–2076. 2. Schiffman M, Castle PE. Human papillomavirus: Epidemiology and public health. Arch Pathol Lab Med . 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: Diagnosis, treatment, and prevention. Clin Infect Dis . 2002;35(suppl 2):S210–S224. 4. Clifford GM, Smith JS, Aguado T, Franceschi S. Comparison of HPV type distribution in high - grade cervical lesions and cervical cancer: A meta - analysis. Br J Cancer . 2003:89;101–105. 5. Mu ñ oz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med . 2003;348: 518–527.
- Key Point The discovery of the link between HPV and cervical cancer developed slowly over the past 20 years based on advances in cellular, molecular, and immunological diagnostic technologies. Background Over the past 20 years, several lines of evidence converged to identify HPV as a cause of cervical cancer. The finding of HPV genomes in cervical carcinomas was a key discovery in the late 1970s. HPV was cloned, and its family defined as large and closely related. The mechanisms of HPV transformation were elucidated, and it was demonstrated that HPV is a true “tumor virus,” carrying genes encoding multiple proteins that interfere with cell cycle control and lead to transformation and uncontrolled cell growth. 1 The link between cervical cancer and HPV was validated by evidence found in epidemiological case - control studies. The data from 1 large, case - control study of 500 women with cervical intraepithelial neoplasia (CIN) and 500 controls by Schiffman and colleagues showed that the majority (76%) of all CIN grades were attributable to HPV infection. 2 Mu ñoz and colleagues conducted a study of 436 cases of histologically confirmed invasive cervical cancer and 387 controls that indicated there was a strong association between certain types of HPV (16, 18, 31, 33, and 35) and invasive cervical cancer. 3 Currently, there are over 100 known types of HPV, 4 of which 30 – 40 affect the anogenital area and 15 –20 are classified as oncogenic . 4,5 Studies have shown that HPV is found in 90% –100% of cervical cancer specimens. 6 References 1. Jansen KU, Shaw AR. Human papillomavirus vaccines and prevention of cervical cancer. Annu Rev Med. 2004;55:319 –331. 2. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst . 1993;85:958–964. 3. Mu ñoz N, Bosch FX, de Sanjosé S, et al . The causal link between human papillomavirus and invasive cervical cancer: A population - based, case - control study in Colombia and Spain. Int J Cancer . 1992;52:743 –749. 4. Schiffman M, Castle PE. Human papillomavirus: Epidemiology and public health. Arch Pathol Lab Med . 2003;127:930–934. 5. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: Diagnosis, treatment, and prevention. Clin Infect Dis . 2002;35(suppl 2):S210–S224. 6. Bosch FX, de Sanjosé S. Human papillomavirus and cervical cancer—Burden and assessment of causality. J Natl Cancer Inst Monogr. 2003;31:3–13.