Biology And Pathophysiology Of Cancer


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  • 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.
  • Biology And Pathophysiology Of Cancer

    1. 1. Biology of Cancer Pathophysiology of Cancer Raul H. Morales-Borges, M.D., FICPS, FIACATH Ashford Institute of Hematology & Oncology
    2. 3. Introduction <ul><li>Cancer is a leading cause of death and source of morbidity of adults in the Western world. </li></ul><ul><li>There are many causes including environment, heredity, and behavior interactions. </li></ul>
    3. 4. Introduction <ul><li>All malignant cells arise from a transformation of a normal cell into an immortal cell which growth uncontrolled. </li></ul><ul><li>Such transformation occurs when the genetic blueprint - the cell’s DNA - is damaged or altered. </li></ul><ul><li>Every cell contain a series of genetic markers known as protooncogenes. </li></ul>
    4. 5. Introduction <ul><li>Tumor development is a multistep process. </li></ul><ul><li>Molecular research is providing interesting new modalities of treatments. </li></ul><ul><li>Management is multidisciplinary. </li></ul><ul><li>Our goals should be prevention, early detection, and provide good quality of life. </li></ul>
    5. 6. Cancer <ul><li>Cancer = Karkinoma, Crab (Cangrejo) </li></ul><ul><li>Neoplasm = New Growth (Crecimiento Nuevo) </li></ul><ul><li>Oncos = Tumor </li></ul>
    6. 7. Definition from 1922 <ul><li>It is a tissue overgrowth independently from the governing laws of the body. </li></ul>
    7. 8. Caracteristicas de Tumor Benigno <ul><li>Crecimiento lento </li></ul><ul><li>Son bien diferenciados </li></ul><ul><li>Tienen una capsula bien definida </li></ul><ul><li>No invasion a otros tejidos </li></ul><ul><li>No metastasis </li></ul>
    8. 9. Ejemplos de tumores benignos <ul><li>Papiloma </li></ul><ul><li>Adenoma </li></ul><ul><li>Cystadenoma </li></ul><ul><li>Nevus </li></ul><ul><li>Neurofibroma </li></ul><ul><li>Lipoma </li></ul><ul><li>Hemangioma </li></ul><ul><li>Linfangioma </li></ul><ul><li>Fibromatosis (desmoide) </li></ul><ul><li>Osteoma </li></ul><ul><li>Condroma </li></ul><ul><li>Leiomioma </li></ul><ul><li>Rhabdomioma </li></ul><ul><li>Meningioma </li></ul>
    9. 10. Caracteristicas de Tumor Maligno <ul><li>Proliferacion de celulas neoplasticas </li></ul><ul><li>No encapsulados </li></ul><ul><li>Pierden la diferenciacion </li></ul><ul><li>Estroma de soporte </li></ul><ul><li>Neovascularizacion (vasos sanguineo nuevos) </li></ul><ul><li>Invasion y Metastasis </li></ul>
    10. 11. Ejemplos de tumores malignos <ul><li>Carcinoma </li></ul><ul><li>Adenocarcinoma </li></ul><ul><li>Melanoma </li></ul><ul><li>Seminoma </li></ul><ul><li>Mieloma </li></ul><ul><li>Linfoma </li></ul><ul><li>Leucemias </li></ul><ul><li>Condrosarcoma </li></ul><ul><li>Neuroblastoma </li></ul><ul><li>Retinoblastoma </li></ul><ul><li>Tumor de Wilm </li></ul><ul><li>Tumor de Ewing </li></ul><ul><li>Mesotelioma </li></ul><ul><li>Sarcoma </li></ul><ul><li>Fibrosarcoma </li></ul><ul><li>Angiosarcoma </li></ul>
    11. 12. Estadios de Tumores malignos <ul><li>Depende del tamano del tumor, nodulos linfaticos y metastasis </li></ul><ul><li>Estadio I – pequeno </li></ul><ul><li>Estadio II – algo mas grande, algunos nodulos </li></ul><ul><li>Estadio III – invasion de estructuras vecinas, mas nodulos </li></ul><ul><li>Estadio IV - metastasis </li></ul>
    12. 13. Carcinoma in situ (CIS) <ul><li>Pre-invasive epithelial malignant tumors of glandular or squamous cell origin. </li></ul><ul><li>Localized to the epithelium. </li></ul><ul><li>No broken local basement membrane. </li></ul><ul><li>No invasion of surrounded tissues. </li></ul><ul><li>Seen in the cervix, beast, skin, oral cavity, esophagus, stomach, bronchus. </li></ul>
    13. 14. Cancer Cells: Transformation <ul><li>Transformation means the process by which a cell becomes cancerous. </li></ul><ul><li>Autonomy is when the cancer cell is independently from normal cellular controls. Cancerous cells show uninhibited growth. </li></ul><ul><li>They are often anchorage-independent (they divide even in a soft agar gel). </li></ul><ul><li>They are usually immortal. </li></ul>
    14. 15. Cancer Cells: Differentiation <ul><li>Differentiation refers to the process of acquiring a specialized function and organization. </li></ul><ul><li>Anaplasia is the absence of differentiation. It is recognized by a loss of organization and a marked increase in nuclear size, with evidence of ongoing proliferation. The cells are of variable size and shape ( pleomorphism ). </li></ul>
    15. 16. Cancer Stem Cells <ul><li>Two characteristics: Self-renew & Multipotent. </li></ul><ul><li>When a stem cell divides, each daughter cell has a choice: </li></ul><ul><ul><li>It can either continue as a stem cell or go on to become terminally differentiated, that is, completely matured (e.g., neuron, myocyte, erythrocyte). </li></ul></ul>
    16. 17. Grado de Tumores <ul><li>Grado I – Bien diferenciados </li></ul><ul><li>Grado II – Moderadamente diferenciados </li></ul><ul><li>Grado III – Pobremente diferenciados </li></ul><ul><li>Grado IV - Anaplasticos </li></ul>
    17. 18. The Genetic Basis of Cancer <ul><li>Clonal selection : Cancer is a disease of aging because the cells acquires a number of genetic mutations over time and the cells then may have a selective advantage over its mutant neighbors ( Clonal proliferation or clonal expansion ). </li></ul>
    18. 19. Malignant Cell Proliferation
    19. 20. Carcinogenesis
    20. 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
    21. 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
    22. 23. Oncogenes and Tumor-suppressor genes <ul><li>Oncogenes are mutant genes that in their normal nonmutant state direct synthesis of proteins that positively regulate proliferation. </li></ul><ul><li>Tumor-suppressor genes encode proteins that in their normal state negatively regulate proliferation. </li></ul>
    23. 24. <ul><li>It’s an oncogene in a normal, nonmutant state. </li></ul><ul><li>The protooncogenes serve to many basic functions to the normal cell such as: growth, maturation and proliferation </li></ul><ul><li>However, such protooncogenes can be altered and become Oncogenes </li></ul><ul><li>Such Oncogenes confers certain characteristic to the cell : uncontrolled growth, invasiveness and immortality </li></ul>PROTOONCOGENES
    24. 25. <ul><li>How does the change from protooncogenes to Oncogenes occur? </li></ul><ul><li>There are several steps toward the malignant transformation of a cell </li></ul><ul><ul><li>Non-lethal genetic damage lies at the heart of carcinogenesis </li></ul></ul><ul><ul><ul><li>A genetic damage ( mutation ) may be acquired by the action of environmental agents such as chemicals, radiation or viruses, or it may be inherited </li></ul></ul></ul>
    25. 26. <ul><ul><li>Two classes of normal regulatory genes - the growth promoting protooncogenes and the growth inhibiting genes ( antioncogenes ) - are the principal targets of genetic damage </li></ul></ul><ul><ul><li>Carcinogenesis is a multistep process at both the phenotypic and genetic level </li></ul></ul><ul><ul><li>Every human cancer that has been analyzed reveals multiple genetic alterations involving activation of several Oncogenes and inactivation of two or more antioncogenes </li></ul></ul>
    26. 27. <ul><li>The genetic damage that activates Oncogenes may be subtle or large enough to be detected in a gross chromosomal analysis: a karyotype analysis. </li></ul><ul><li>In some cancers such alterations are nonrandom and common </li></ul><ul><li>Specific alterations have been identified for most leukemia's and lymphomas </li></ul>
    27. 28. <ul><li>The most common types of such alterations are: </li></ul><ul><ul><li>translocations </li></ul></ul><ul><ul><li>deletions </li></ul></ul><ul><ul><li>gene amplification </li></ul></ul><ul><ul><li>point mutations </li></ul></ul>
    28. 29. Point Mutations <ul><li>They are the most common events in small scale changes in DNA. </li></ul><ul><li>It’s an alteration of one or a few nucleotide base pairs. </li></ul><ul><li>e.g., ras gene is associated with pancreatic and colorectal cancer. </li></ul>
    29. 30. Chromosome Translocation <ul><li>It can cause excess and inappropriate production of a proliferation factor (e.g., t(8;14) in Burkitt lymphomas) such as MYC protein. </li></ul><ul><li>It can also lead to production of novel proteins with growth promoting properties (e.g., t(9;22) in CML) such as BCR-ABL protein. </li></ul>
    30. 31. Gene Amplification <ul><li>Result of duplication of a small piece of a chromosome over and over again, so that instead of normal two copies of a gene, tens or even hundreds of copies are present. </li></ul><ul><li>Results in increased expression of an oncogene, or in some cases, drug resistance genes. </li></ul><ul><li>E.g.: N-myc in Neuroblastoma & erb2 in Breast cancer. </li></ul>
    31. 32. Tumor-Suppressor genes <ul><li>They are genes whose major function is to negatively regulate cell growth and prevent mutations. </li></ul><ul><li>Needs two (2) mutational events to contribute to the cancer. </li></ul><ul><li>Loss of function, acts in recessive fashion. </li></ul><ul><li>Inherited form is common and has a tissue preference. </li></ul><ul><li>Examples: p53 (GBM, SCLC, BCA, CRC), Rb (retinoblastoma), APC & MCC (CRC). </li></ul>
    32. 33. Loss of heterozygosity <ul><li>Loss of a chromosome region in a tumor. </li></ul><ul><li>Unmasks inactivating mutations in recessive tumor suppression genes. </li></ul><ul><li>Also named as allelic loss. </li></ul><ul><li>Examples: LOH for 5q for sporadic adenomas to carcinomas, Loss of the 13q14 chromosome region on one chromosome for Rb. </li></ul>
    33. 34. Gene Silencing <ul><li>The epigenetic silencing is associated with methylation of both the DNA and associated chromatin. So, no functional protein will be produced. </li></ul>
    34. 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
    35. 36. <ul><li>In the near past, our understanding of cellular function was rudimentary </li></ul><ul><li>Now, our knowledge of cells has progressed to an understanding of many complex interactions and networks: </li></ul><ul><ul><li>extracellular </li></ul></ul><ul><ul><li>intracellular </li></ul></ul><ul><ul><li>intranuclear </li></ul></ul>
    36. 37. <ul><li>The genome project has amplified this capacity through numerous techniques, including the cluster array analysis </li></ul><ul><li>Breast cancer cells are now classified in five groups </li></ul><ul><ul><li>basal like - null cell </li></ul></ul><ul><ul><li>erb2+ A & B </li></ul></ul><ul><ul><li>normal </li></ul></ul>
    37. 38. Alterations in progrowth and antigrowth <ul><li>Cancer cells have mutations that enable them to proliferate in the absence of external growth signals. To achieve this, some caner cells acquire the ability to secrete growth factors that stimulate their own growth ( Autocrine stimulation). </li></ul><ul><li>Other have an increase in growth factor receptors (EGFR), an activating mutation in an intracellular signaling protein called ras, an antigrowth signaling such as Rb, and a self-destruction mechanism such as apoptosis (p53). </li></ul>
    38. 39. Angiogenesis <ul><li>Neovascularization is a characteristic of cancer cells to provide their own new vessel supply. It’s secondary to purified angiogenic factors such as bFGF & VEGF. </li></ul><ul><li>Vascular endothelial growth factor is angiogenic in vivo for endothelial cells. </li></ul><ul><li>Basic fibroblast growth factor is mitogenic for vascular endothelial cells and is strongly angiogenic. </li></ul>
    39. 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
    40. 41. Telomeres <ul><li>They are protective ends, or caps, on each chromosome and are placed and maintained by a specialized enzyme called telomerase . </li></ul><ul><li>Telomerase is usually active only in germ cells in ovaries and testes and in stem cells. </li></ul><ul><li>When the telomeres become critically small, the chromosomes become unstable and fragment, then the cells die. Cancer cells at critical activate telomerase to restore and maintain their telomere to survive and divide. </li></ul>
    41. 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*
    42. 43. Prognostic and predictive factors <ul><li>p53 status </li></ul><ul><li>Other cell cycle components including p27, p15, p16, pRb, cyclin and CDK </li></ul><ul><li>K-ras mutations </li></ul><ul><li>HER2/neu and epidermal growth factor receptor (EGFR) </li></ul><ul><li>Beta tubulin </li></ul><ul><li>Expression of matrix metalloproteinase and inhibitors </li></ul><ul><li>DNA topoisomerase II  and II  </li></ul><ul><li>Single nucleotide polymorphism in myeloperoxidase gene reduces risk of lung cancer </li></ul><ul><li>Heparin-binding growth factor pleiotrophin </li></ul>
    43. 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
    44. 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
    45. 46. Human Cancer & Family Genetics <ul><li>Germline mutations. </li></ul><ul><li>Inheritance of a mutated gene that can cause cancer. </li></ul><ul><li>Examples: Neuroblastoma, Wilm’s tumor, Neurofibromatosis, Breast Cancer, Familial Polyposis coli or Adenomas of the colon. </li></ul>
    46. 47. Causas Hereditarias <ul><li>Neurofibromatosis (Enfermedad de von Reckinghausen) : Neurofibro-sarcomas </li></ul><ul><li>Sindrome de Gardner : Fibro-sarcomas desmoides del mesenterio </li></ul><ul><li>Retinoblastoma familiar : Osteo-sarcomas </li></ul><ul><li>Sindrome Familiar de Li-Fraumeni </li></ul><ul><li>Sindrome de Stewart-Treves -Angiosarcomas </li></ul><ul><li>Hemocromatosis </li></ul>
    47. 48. Causas Geneticas de Sarcomas <ul><li>Translocaciones: t(11;22), t(12;14), t(2;13), t(X;18), t(12;16) </li></ul><ul><li>Expesion de MDR 1 </li></ul><ul><li>Mutaciones: genes p53, Rb </li></ul><ul><li>Deleciones: 1p-, 3p-, 13q- </li></ul><ul><li>Proto-oncogenes: c-myc, N-myc, c-myb, c-mil/raf-1, c-fes, c-sis </li></ul>Pathologe 17(3):195-201, 1996 Diagnostic Molecular Pathology 5(2):98-106, 1996 Monographs in Pathology 38:65-128, 1996 American J of Pathology 150(6):1997-2007, 1997 Seminars in Oncology 24(5):515-525, 1997 J Cancer Research & Clinical Oncology 123(4):211-8, 1997
    48. 49. Inflammatory Conditions & Cancer Reactive Oxygen Species Increased COX2 Proliferation Release of growth factors Release of cytokines Injury Cancer
    49. 50. Chronic Inflammation & Cancer <ul><li>Chronic Ulcerative Colitis : Colon Cancer </li></ul><ul><li>Chronic Hepatitis B or Hepatitis C : Liver Cancer </li></ul><ul><li>COPD, Chronic asthma : Lung Cancer </li></ul><ul><li>Chronic Cystitis : Bladder Cancer </li></ul><ul><li>Sjogren syndrome : Lymphoma </li></ul><ul><li>Chronic Thyroiditis : Lymphoma </li></ul><ul><li>Fibrocystic Breast Disease : Breast Cancer </li></ul><ul><li>Benign Prostate Hyperplasia : Prostate Cancer </li></ul>
    50. 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)
    51. 52. Benign Breast Disease may not be so benign <ul><li>From Mayo Clinic Cancer Center </li></ul><ul><li>If developed before 40 y/o the risk of BCA can increase by 83% and if we add a strong family history the risk increases by 93%. </li></ul>
    52. 53. Viral Infections & Cancer <ul><li>Ellerman in Denmark in 1908 and Rous in 1911: Retrovirus and Avian leukemia & Avian sarcoma. </li></ul><ul><li>Hepatitis B & C viruses – Hepatocellular carcinoma </li></ul><ul><li>Herpes virus / Epstein-Barr – Burkitt lymphoma, nasopharyngeal carcinoma </li></ul><ul><li>KSHV / HHV-8 – Kaposi sarcoma </li></ul><ul><li>HPV – Cervical and anogenital carcinoma </li></ul><ul><li>Retrovirus </li></ul><ul><ul><li>HTLV-1 – Adult-T-cell leukemia/lymphoma </li></ul></ul><ul><ul><li>HTLV-2 – Hairy- cell leukemia </li></ul></ul><ul><ul><li>HIV – Kaposi sarcoma </li></ul></ul>
    53. 54. HEAD & NECK CANCER Nasopharyngeal cancer and Epstein-Barr virus <ul><li>Endemic in regions of Northern Africa and Asia </li></ul><ul><li>Etiology distinct from other head and neck cancers </li></ul><ul><li>Epstein-Barr viral proteins detectable in majority of nasopharyngeal tumors </li></ul><ul><li>Associated with frequent consumption of salted fish or nitrosamines </li></ul>Stupp R, Vokes EE. Current Cancer Therapeutics. 3rd ed. 1998;165-166.
    54. 55. HPV <ul><li>>100 types identified 2 </li></ul><ul><li>30–40 anogenital 2,3 </li></ul><ul><ul><li>15–20 oncogenic* ,2,3 types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 58 4 </li></ul></ul><ul><ul><ul><li>HPV 16 (54%) and HPV 18 (13%) account for the majority of worldwide cervical cancers. 5 </li></ul></ul></ul><ul><ul><li>N ononcogenic † types include: 6, 11, 40, 42, 43, 44, 54 4 </li></ul></ul><ul><ul><ul><li>HPV 6 and 11 are most often associated with external genital warts. 3 </li></ul></ul></ul>1. Howley PM . In: Fields BN, Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott - Raven; 1996:2045–2076. 2. Schiffman M, Castle PE. Arch Pathol Lab Med . 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis . 2002;35(suppl 2):S210–S224. 4. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med . 2003;348:518–527. 5. Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer . 2003:89;101–105. Nonenveloped double - stranded DNA virus 1 <ul><ul><ul><li>*High risk; † Low risk </li></ul></ul></ul>
    55. 56. Discovery of the Link Between HPV and Cervical Cancer 1. Jansen KU, Shaw AR. Annu Rev Med . 2004;55:319–331. 2. Schiffman M, Castle PE. Arch Pathol Lab Med . 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis . 2002;35(suppl 2):S210–S224. <ul><li>Body of information developed slowly based on advances in cellular, molecular, and immunological diagnostic technologies over the past 20 years 1 </li></ul>Epidemiological case - control studies completed 1 HPV defined as large, closely related family 1 : >100 types 2 ; 30 –40 anogenital 2,3 HPV genomes found in cervical carcinomas 1 HPV viruses cloned 1 Mechanisms of transformation elucidated (true “tumor virus”) 1 15–20 HPV types classified as oncogenic 2,3
    56. 57. Link Between HPV and Cervical Cancer <ul><li>99% of Cervical cancers and High-grade cervical cancer precursor lesions associated with HPV </li></ul><ul><li>Risk for developing cervical cancer with HPV is 50-100x higher than without HPV infection </li></ul><ul><li>Risk of High-grade precursor lesion with HPV is 300-fold </li></ul>
    57. 58. Bacterial – Parasitic Infection & Cancer <ul><li>Helicobacter pylori – Gastric cancer, MALT </li></ul><ul><li>Opisthorchis viverrini – Cholangio-carcinoma </li></ul><ul><li>Schistosoma haematobium – Bladder carcinoma </li></ul>
    58. 59. Environmental Factors & Cancer <ul><li>Carcinogens are agents that can cause cancer. </li></ul><ul><li>Xenobiotics are toxic, mutagenic, and canrcinogenic chemicals </li></ul><ul><li>Important factors to be considered are: time of exposure, racial & gender disparities, human contamination & public health advocacy </li></ul><ul><li>Tobacco smoke has polycyclic aromatic hydrocarbons, nitroso compounds, arylamines, benzo(a) pyrene metabolites, and benzene which are potent carcinogens. </li></ul>
    59. 60. Causas de Sarcomas <ul><li>Exposicion a Radioterapia </li></ul><ul><li>Pacientes inmunocomprometidos </li></ul><ul><li>Exposicion a quimicos como hidro-carburos policiclicos, cloruro de polivinil, asbestos, dioxina de los herbicidas. </li></ul><ul><li>Cicatrices de cirugias previas, quemaduras, dano e implantacion de cuerpo extrano </li></ul><ul><li>Hespes virus 8, HIV, HTLV-III, Rous Sarcoma virus </li></ul><ul><li>Tumores Benignos de huesos: condromas, displasia fibrosa, Enfermedad de Paget del hueso </li></ul>
    60. 61. Tobacco & Related Cancers <ul><li>Lung </li></ul><ul><li>Oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, esophagus & stomach </li></ul><ul><li>Pancreas & Liver </li></ul><ul><li>Penis, kidney, bladder </li></ul><ul><li>Cervix uteri </li></ul><ul><li>Myeloid leukemia </li></ul>
    61. 62. Radiation & Cancer <ul><li>20 to 250 cGy for linear energy transfer radiation, such as x-rays or gamma-rays is the human cancer risk dose. </li></ul><ul><li>Radiation-induced gene mutations or chromosomal abnormalities that can be detected early (within 24 hours of radiation exposure) are not solely responsible for tumor development in normal human cells. </li></ul>
    62. 63. Genomic instability & Radiation Bystander effect & Gap Junction Intercellular Communication Mitotic failure Cell death Chromosome alteration Gene mutation DNA damage Ionizing radiation
    63. 64. Ultraviolet radiation & Skin Cancer <ul><li>It causes melanoma, basal cell carcinoma and squamous cell carcinoma of the skin. </li></ul><ul><li>The degree of damage depends on the intensity and wavelength content and the depth of penetration. </li></ul><ul><li>It induces release of tumor necrosis factor in the epidermis. </li></ul><ul><li>Inflammation is a critical component through hydrogen peroxide. </li></ul><ul><li>Activation of the mitogen-activated protein kinase (MAPK) (eg. Melanoma) </li></ul>
    64. 65. Multistep skin Carcinogenesis Protein oxidation Lipid peroxidation Xenobiotics Mutate protooncogenes Inflammation ROS Direct DNA Damage UVR Oxidative Stress
    65. 66. Alcohol Consumption <ul><li>Associated with cancer of the: oral cavity, pharynx, hypopharynx, esophagus, liver, breast, colorectum. </li></ul><ul><li>Mechanisms: effect of acetaldehyde, induction of cytochrome P-4502 E1 leading to the generation of ROS, increased procarcinogen activation, modulation of cellular regeneration, nutritional deficiency, altered mucosal integrity, enzyme and metabolic dysfunction, structural abnormalities. </li></ul>
    66. 67. Physical Activity <ul><li>Related with breast and colon cancers. </li></ul><ul><li>Mechanisms: increases insulin and insulin-like growth factors, obesity, decreasing free radical scavenger systems, inflammatory mediators, increasing estrogen and androgens, decreasing gut motility. </li></ul><ul><li>Rx: for CRC we need 3.5 – 4 hours/week, for BCA we need 30 – 60 minutes /day. </li></ul>
    67. 68. Diet & Obesity <ul><li>Important risk factors: low fiber and high fat diet, obesity, alcohol consumption, contaminated corn, peanuts and rice with aflatoxin, Chinese-style salted fish, hot beverages, grilled meat, red or processed food. </li></ul><ul><li>Overweight and obesity are linked with cancer of: breast, colorectal, esophagus, gastric, liver, gallbladder, pancreas, prostate, uterine, cervix, ovaries, non-Hodgkin’s lymphoma, multiple myeloma, leukemia. </li></ul>
    68. 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
    69. 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
    70. 71. Air Pollution <ul><li>Indoor pollution is worse than outdoor pollution. </li></ul><ul><li>Indoor pollutants: </li></ul><ul><ul><li>Environmental Tobacco Smoke </li></ul></ul><ul><ul><li>Radon gas (lung cancer) </li></ul></ul><ul><ul><li>Inorganic Arsenic (bladder, skin, and lung cancers) </li></ul></ul>
    71. 72. Electromagnetic fields <ul><li>It’s controversial, little evidence is available. Further research is needed. </li></ul><ul><li>Some association: Leukemia in children & Brain Tumor in adults. </li></ul><ul><li>EMR -> Thermal effect -> Protein phosphorylation (?) </li></ul>
    72. 73. Occupational Carcinogens <ul><li>Asbestos: mesothelioma, lung cancer </li></ul><ul><li>Chromium, Nickel, Mustard gas: : lung cancer </li></ul><ul><li>Heterocyclic Amines: Colon Cancer </li></ul><ul><li>Dyes, Rubber, Paint, and Aromatic amines: Bladder cancer </li></ul><ul><li>Aflatoxin B, Vinyl chloride: Liver cancer </li></ul><ul><li>Cadmium: Prostate cancer </li></ul><ul><li>Benzol inhalation & leukemia in shoemakers, rubber cement industry, explosives, and dyeing industry. </li></ul>
    73. 74. Therapeutic drugs & Cancer <ul><li>Alkylating agents: melphalan, myleran – AML </li></ul><ul><li>MOPP – AML </li></ul><ul><li>Immunosuppressants: azathioprine and cyclosporin – Lymphoma </li></ul><ul><li>Phenacetin – Renal & Bladder cancer </li></ul><ul><li>Hormones (estrogen, OCP’s, tamoxifen) – Endometrial carcinoma </li></ul>
    74. 75. Tumor Spread, Invasion & Metastasis <ul><li>Direct Invasion (local) </li></ul><ul><ul><li>Cellular multiplication, mechanical pressure, release of lytic enzymes, decreased cell to cell adhesion, increased motility of cells, disruption of tumor-host microenvironment </li></ul></ul><ul><li>Metastases to distant organs through lymphatic and blood system </li></ul><ul><li>Metastases by way of implantation (tissue spaces, body cavities, cerebrospinal spaces) </li></ul>
    75. 76. Tumor Invasion & Metastasis <ul><li>Anoikis: homelessness – cells detach from their matrix and undergo apoptosis. </li></ul><ul><li>Lytic enzyems are: Matrix metallo-proteinases such as type IV collagenase, Cysteine proteinases such as cathepsin b and D, and Serine proteases such as urokinase-type plasminogen activator. </li></ul><ul><li>Incresed expression of Twist expression causes a loss of E-cadherin-mediated cell to cell adhesion. </li></ul><ul><li>Three step theory of invasion: attachment, degradation, and locomotion of the matrix. </li></ul>
    76. 77. Clinical Manifestations of Cancer (IL-1, TNF, IL-6, IFN) <ul><li>Pain is one of the main complaints. 25% of all cancer patients die with unrelieved pain. </li></ul><ul><li>Fatigue is a second complaint. </li></ul><ul><li>Cachexia is from IL-6, IL-8, TNF. </li></ul><ul><li>Anemia is secondary to TNF, IL-1, decreased EPO, impaired iron utilization, and chemo/radio. </li></ul><ul><li>Nausea & Vomiting is usually 2ry to chemo. </li></ul><ul><li>Depression, anxiety, and delirium occurs in 50% of patients. </li></ul>
    77. 78. Paraneoplastic Syndromes <ul><li>Seen in 10% of cancer patients. </li></ul><ul><li>Endocrine Manifestations: </li></ul><ul><ul><li>Ectopic ACTH (Cushing’s): SCLC, Bronchial carcinoid </li></ul></ul><ul><ul><li>SIADH: Lung cancer </li></ul></ul><ul><ul><li>Hypercalcemia: Lung (Sq.), Renal, Myeloma, ATCLL </li></ul></ul><ul><li>Hematologic Manifestations: </li></ul><ul><ul><li>Polycythemia: Renal, Liver </li></ul></ul><ul><ul><li>DVT/PE: Pancreas, Lung </li></ul></ul><ul><li>Gastrointestinal Manifestations: </li></ul><ul><ul><li>Protein-losing enteropathy </li></ul></ul><ul><ul><li>Anorexia, Cachexia </li></ul></ul><ul><li>Renal Manifestations: </li></ul><ul><ul><li>Membranous nephropathy: stomach, lung, colon </li></ul></ul><ul><li>Cutaneous: </li></ul><ul><ul><li>Acanthosis nigricans: GI cancer (Leser-Trelat) </li></ul></ul><ul><ul><li>Dermatomyositis: Breast & Bronchogenic ca. </li></ul></ul><ul><li>Neurologic: </li></ul><ul><ul><li>Myasthenia: Bronchogenic ca. </li></ul></ul><ul><li>Rheumatologic: </li></ul><ul><ul><li>Hyperthtophic osteoarthropathy: Bronchogenic ca. </li></ul></ul>
    78. 79. Tumor markers (Biologic markers) <ul><li>They are substances produced by cancer cells that are found on tumor plasma membranes or in the blood, spinal fluid, or urine. </li></ul><ul><li>AFP : Liver, Germ cell tumors </li></ul><ul><li>B-HCG: Germ cell tumors </li></ul><ul><li>CEA: Colon, Pancreas, Lung, breast </li></ul><ul><li>PSA: Prostate </li></ul><ul><li>CA19-9: Pancreas, Billiary tree </li></ul><ul><li>CA 125: Ovarian </li></ul><ul><li>CA 15-3 or CA 27.29: Breast </li></ul><ul><li>B-2-microglobulin: Myeloma, Lymphoma </li></ul><ul><li>Catecholamines: Pheochromocytoma </li></ul>
    79. 80. FDG-PET Scanning <ul><li>FDG is a glucose analog that is taken up and trapped by tumor cells in most of patients with cancer. The positrons emitted by the F18 atom travel a short distance before they encounter an electron and undergo extinction with emission of a pair of photons in opposite directions. </li></ul>
    80. 81. Significance of FDG-PET scan <ul><li>Adds assessment to uncharacterized nodules and more accurately stages the tumor than CT. </li></ul><ul><li>Intensity of uptake before tx is correlated with survival: high uptake = negative prognosis. </li></ul>
    81. 82. More about PET <ul><li>It is a complement to CT in instances where CT has failed to detect distant metastatic disease, and advising biopsies for LN’s > 1.0 cm on CT or positive on FDG-PET. Biopsy is still advised for radio-graphically enlarged LN’s even if FDG-PET scanning is negative. </li></ul>
    82. 83. Cancer treatment <ul><li>Surgery is the goal standard. </li></ul><ul><ul><li>Colorectal, Breast, Ovary, Lung, Thyroid, Skin, Uterus, Prostate </li></ul></ul><ul><li>Chemotherapy: Lymphoma, Leukemia, Testicular, Choriocarcinoma, Ovary, Breast </li></ul><ul><li>Radiation therapy: Breast, Uterus, Cervix, Lymphoma, Lung </li></ul><ul><li>Hormonal therapy: Breast, Prostate, Endometrial, Adrenal </li></ul><ul><li>Immunotherapy: Melanoma, RCC, Leukemia </li></ul><ul><li>Target therapy: Colon, Breast, Lung, RCC, Leukemia, Lymphomas </li></ul>
    83. 84. Progress in Oncology <ul><li>New diagnostic methods </li></ul><ul><li>Preventive Medicine </li></ul><ul><li>New Targeted and Personalized Therapy </li></ul><ul><li>Palliative & Supportive Care </li></ul>
    84. 85. THANK YOU !!!