PATHOBIOLOGY OF NEOPLASIA

Transcription

1 PATHOBIOLOGY OF NEOPLASIA Department of Pathology Gadjah Mada University School of Medicine dr. Harijadi Blok Biomedis, 6 Maret 2009 [12] 3/17/2009 1

2 The pathobiology of neoplasia Normal cells Malignant cells Changes: Genotypic Phenotypic 3/17/2009 2

3 Neoplasia Neoplasia new growth Neoplasm: abnormal tissue mass growing excessively and indefinitely without coordination with normal tissue Behaviour: progressive, useless, independent from surrounding tissue, unrelated to host needs, parasitic, autonomic. 3/17/2009 3

4 PATHOBIOLOGY OF TUMOR GROWTH The tumor cells tend to replicate rather than to differentiate due to genetic alterations (oncogene activation, anti-oncogene suppression, etc) Most tumors are of monoclonal origin 3/17/2009 4

5 CARCINOGENESIS: The Molecular basis of Cancer Nonlethal genetic damage lies at the heart of carcinogenesis 3 classes of normal regulatory genes: growth promoting (proto-oncogenes), anti-oncogenes (growth inhibiting / suppressor genes), apoptotic genes (regulate programmed cell death) the principal targets of genetic damage. DNA repair genes, affect cell proliferation or survival indirectly by influencing the ability of the organism to repair non-lethal damage of other genes. Carcinogenesis is a multi-step process at both the genetic and phenotypic level 3/17/2009 5

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7 CANCER SUPPRESSOR GENES Misnomer Physiologic function: regulate cell growth (not to prevent tumor formation) apply brakes to cell proliferation Discovered by studying rare disease such as retinoblastoma Knudson Hypothesis as a paradigm for two-hit hypothesis of oncogenesis apply substantiated by other suppressor gene, and now can be formulated in more precise terms, using retinoblastoma as paradigm 3/17/2009 7

8 CANCER SUPPRESSOR GENES Two-hit Hypothysis of Oncogenesis In hereditary cases, one genetic change ( first hit ) is inherited from affected parent present in all somatic cells of the body The second mutation ( second hit ) occurs in one of many retinal cells (which already carry the first mutation) In sporadic case, both mutations (hits) occur somatically within a single cell tumor 3/17/2009 8

9 CANCER SUPPRESSOR GENES: Rb gene Paradigm of: two hit hypothysis of carcinogenesis 3/17/2009 9

10 Role of RB as Cell-cycle Regulator Virtually all cancers show dysregulation of the cell cycle by affecting the four genes (red asterisk) 3/17/

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12 Sub-cellular location of protein product of tumor suppressor genes 2 broad categories regarding the functions: Molecules that regulate nuclear transcription and cell cycle Cell surface: TGF-receptor, E-cadherin Under plasma mebrane: NF-1 Cytoskeleton: NF-2 Cytosol: APC/β-catenin, PTEN, SMAD 2, SMAD 4 Molecules that regulate signal tranduction Nucleus: Rb, p53, WT-1, p16(ink4a), BRCA-1, BRCA-2 3/17/

13 Selected tumor-suppressor gene involved in human neoplasm TGF-β receptor Function: Growth inhibition Tumors associated with somatic mutation: Carcinoma of colon Tumors associated with inherited mutation: Unknown 3/17/

14 Selected tumor-suppressor gene involved in human neoplasm E-cadherin Function: Cell adhesion Tumors associated with somatic mutation: Ca. gaster & breast Tumors associated with inherited mutation: Familial gastric cancer 3/17/

15 Selected tumor-suppressor gene involved in human neoplasm NF-1 Function: Inhibition of ras signal transduction Tumors associated with somatic mutation: Schwannoma Tumors associated with inherited mutation: Neurofibromatosis type 1 and sarcomas 3/17/

16 Selected tumor-suppressor gene involved in human neoplasm Function: Unknown NF-2 Tumors associated with somatic mutation: Schwannoma and meningioma Tumors associated with inherited mutation: Neurofibromatosis type 2, acoustic schwannoma & meningioma 3/17/

17 Selected tumor-suppressor gene involved in human neoplasm APC Function: Inhibition of signal transduction Tumors associated with somatic mutation: Ca. of stomach, colon, pancreas; melanoma Tumors associated with inherited mutation: Familial Adenomatous Polyposis coli; colon cancer 3/17/

18 Selected tumor-suppressor gene involved in human neoplasm Rb Function: Regulation of cell cycle Tumors associated with somatic mutation: Retinoblastoma, osteosarcoma, Ca breast, colon, lung Tumors associated with inherited mutation: Retinoblastoma, osteosarcoma 3/17/

19 Selected tumor-suppressor gene involved in human neoplasm p53 The guardian of the genome Located on chromosome 17p13.1 The most common target for genetic alteration in human tumors A little over 50% of human tumors contain mutation in this gene 3/17/

20 Selected tumor-suppressor gene involved in human neoplasm Function: p53 Regulation of cell cycle & apoptosis in response to DNA damage Tumors associated with somatic mutation: Ca. gaster & breast Tumors associated with inherited mutation: Li-Fraumeni syndrome Multiple carcinoma and sarcoma 3/17/

21 PATHOBIOLOGY OF TUMOR GROWTH Most malignant tumors normally passing four phases : Transformation Growth of transformed cells Local invasion Distant metastases

22 BIOLOGY OF TUMOR GROWTH Multiple factors that influence tumor growth 1. Kinetics of tumor growth 2. Tumor angiogenesis 3. Tumor prgression and heterogeneity 3/17/

23 BIOLOGY OF TUMOR GROWTH Kinetics of tumor growth How long does it take to produce a clinically overt tumor mass? This depends on three variables: The doubling time of tumor cells Growth fraction Cell production and loss 3/17/

24 Kinetics of tumor growth The doubling time of tumor cells Original transformed cell (+ 10u in diameter) must undergo at least 30 population doublings to produce 10 9 cells (weighing + 1gm) ---- the smallest clinically detectable mass. In contrast, only 10 further doubling cycles are required to produce a tumor containing cells (weighing + 1 kg), which is usually the maximal size compatible with life. 3/17/

25 The doubling time of tumor cells 3/17/

26 Kinetics of tumor growth The doubling time of tumor cells Is the amount of time a tumor to double in cell numbers Doubling time for malignant tumor is not necessarily longer than normal cell origin. Benign tumors grow more slowly One factor in doubling time is the number cells in the growth phase Another factor, is the number of cells that die and never replicated, that is, most cells in a tumor, much more than 90% 3/17/

27 Kinetics of tumor growth The doubling time of tumor cells Characteristics of tumor cells: Cells in the growth phase are the most susceptible to chemotherapeutic agents Type of tumor vary in their doubling time, and the same type of tumor varies from patient to patient 3/17/

28 Kinetics of tumor growth The doubling time of tumor cells A lesson to be learnt from the concept of doubling time / tumor growth is : by the time a solid tumor is clinically detected, it has already completed a major portion of its life cycle or, When tumors are finally discovered, they have been around for a long time, growing unnoticed because of their small size. By the time the tumor achieves a clinically noticeable size, its rate of growth will become more clinically noticeable 3/17/

29 Kinetics of tumor growth Growth Fraction The proportion of tumor cells within the tumor cell population that are in replicative pool Tumor continue to grow cells leave the replicative pool, owing to: - shedding or lack of nutrient - by differentiating - reversion to G 0 most cells within cancer remain in the G 0 phase In some rapidly growing tumors, the growth fraction is approximately 20% 3/17/

30 Kinetics of tumor growth Growth fraction 3/17/

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32 Telomerase activities and maintenance of telomere length are essential for the maintenance of replicative potential in cancer cells 3/17/

33 Kinetics of tumor growth Cell production and loss Progressive growth of tumors and the rate of growth is determined by how much cell production exceeds cell loss In tumors with relatively high growth fraction, the imbalance is large more rapid growth 3/17/

34 The important clinical implication of tumor cell kinetics Cancer chemotherapy Most antineoplastic agents are mostly effective on cycling cells high growth fraction tumors are very sensitive to anti-cancer drugs Debulking the left cells ten to re-enter the cell cycle sensitive Latent period of tumors Most tumor cells leave replicative pool latent period (months/years before a tumor becomes clinically detectable) 3/17/

35 BIOLOGY OF TUMOR GROWTH Tumor angiogenesis Blood supply : Tumor cannot enlarge beyond 2 mm in diameter or thickness unless they are vascularized. Presumably the 2 mm zone represent the maximal distance across which oxygen and nutrients can diffuse from blood vessels. 3/17/

36 BIOLOGY OF TUMOR GROWTH Tumor angiogenesis Angiogenesis is not only for tumor growth, but also for metastasize Angiogenesis is a necessity for biological correlation of malignancy. Several studies have revealed a correlation between the extent of angiogenesis (microvessel density) and the probable of metastases in melanomas and cancer of the breast,lung,colon and prostate 3/17/

37 BIOLOGY OF TUMOR GROWTH Tumor angiogenesis Effect of neovascularization Perfusion of supply nutrients, oxygen, and newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting polypeptides such as IGF, PDGF, GM-CSF, and IL-1 3/17/

38 BIOLOGY OF TUMOR GROWTH Tumor angiogenesis How do growing tumors develop blood supply Tumor contain factor that are capable of affecting the entire series of events involved in the formation of new capillaries Tumor Associated Angiogenic Factors (TAAF) may be produced by tumor cells or inflammatory cells (macrophage) that infiltrate tumors. TAAF : many, but two most important : VEGF and bfgf --- expressed in wide variety of tumor elevated levels can be detected in the serum and urine 3/17/

39 BIOLOGY OF TUMOR GROWTH Tumor angiogenesis Antiangiogenesis Tumor cells also induced and produced antiangiogenesis molecules. Tumor growth is controlled by the balance between angiogenic factors and antiangiogenic factor (inhibit angiogenesis). Example of Antiangiogenesis : Thrombospondin1 Angiostatin, endostatin, tumstatin 3/17/

40 BIOLOGY OF TUMOR GROWTH Tumor Angiogenesis Dysorganized vessels within the tumor mass 3/17/

41 Tumor angiogenesis compared to normal blood vessel The tumor vasculature is formed from circulating endothelial precursor cells and existing host vessel. Myofibroblasts give rise to pericytes at the periphery of the vessels. The tumor vessels are unstable and leaky. 3/17/

42 Tumor angiogenesis compared to normal blood vessel Arterioles, capillaries, and veins are disorganized and unidentifiable. 3/17/

43 Angiogenesis Because angiogenesis is critical for the growth and spread of tumors, much attention is focused on the use of angiogenesis inhibitors therapy Success has been achieved in treating fairly large tumors in mice by adm. of endostatin and tumstatin (anim.exp.) 3/17/

44 BIOLOGY OF TUMOR GROWTH Tumor progression and heterogeneity Over period of time the tumor become more aggressive and acquire greater malignant potential tumor progression Most malignant tumor are monoclonal in origin but by the time they become clinically evedent, their constituent cells are extremely heterogenous 3/17/

45 Tumor Progression and Heterogeneity 3/17/

46 Malignant potential Acclerated growth, invasiveness, ability to form distant metastasis Invasion and metastasis are biologic hallmark of malignancy Four steps of invasion Detachment of tumor cells Attachment of tumor cells to matrix components Degradation of ECM Migration of tumor cells 3/17/

47 Invasion Sequence of Basement Membrane by Tumor Cells 3/17/

48 The METASTATIC CASCADE 3/17/

49 Mechanism of metastasis development within a primary tumor 3/17/

50 Resume Tumor growth Tumor cells do not necessarily proliferate more rapidly than their normal counterpart The major determinant of tumor growth is clearly the fact that more cells are produced than die in a given time 3/17/

51 Resume The growth of cancer Tumor growth rates may be expressed as doubling time Tumor angiogenesis refers to the sprouting of new capillaries Tumor dormancy accounts for interval before the appearance of metastasis 3/17/

52 Resume Tumor dormancy Often, metastatic tumors is not detectable at the time of the removal of a primary tumor Breast cancer and melanoma metastasis may remain dormant for many years It is not known whether they remain in G 0 phase of cell cycle for prolonged period of time or whether they do not grow because interference with angiogenesis, unresponsiveness to growth factors, or the presence immune growth restraints 3/17/

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