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牙科公共衛生學 Prevention & detection of oral cancer 口腔癌之預防與偵測 陳玉昆副教授 : 高雄醫學大學 口腔病理科 07-3121101~2755

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Presentation on theme: "牙科公共衛生學 Prevention & detection of oral cancer 口腔癌之預防與偵測 陳玉昆副教授 : 高雄醫學大學 口腔病理科 07-3121101~2755"— Presentation transcript:

1 牙科公共衛生學 Prevention & detection of oral cancer 口腔癌之預防與偵測 陳玉昆副教授 : 高雄醫學大學 口腔病理科 07-3121101~2755

2 參 考 書 目參 考 書 目 1.Gibbs WW. Untangling the roots of cancer. Sci Am 2003;289:56-65. 2.What you need to know about cancer. Sci Am 1996 ;289:28-119. 3. Hannen EJM, Riediger D. The quantification of angiogenesis in relation to metastasis in oral cancer: a review. Int. J Oral Maxillofac Surg 2004;33:2-7. 4.Shieh et al. Role of angiogenic and non-angiogenic mechanisms in oral squamous cell carcinoma: correlation with histologic differentiation and tumor progression. J Oral Pathol Med 2004;33:601-6. 5.Sharma DC. Betel quid and areca nut are carcinogenic without tobacco. Lancet Oncol 2003;4:587. 6.Sharma DC. Indian betel quid more carcinogenic than anticipated. Lancet Oncol 2001;2:464. 7.Braakhuis BJM et al. A genetic progression model of oral cancer: current evidence and clinical implications. J Oral Pathol Med 2004;33:317-22. 8.Braakhuis BJM et al. A Genetic explanation of slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 2003;63:1727-30. 9.Loktionov A. Common gene polymorphisms, cancer progression and prognosis. Cancer Letters 2004;208 :1-33. 10.Desmaze C et al. Telomere-driven genomic instability in cancer cells. Cancer Letters 2003;194:173-82. 11.Hiyama E & Hiyama K. Telomerase as tumor marker. Cancer Letters 2003;194:221-33. 12.Kaohsiung Medical University, Oral Pathology Department 13.Huang AH et al. Isolation and characterization of normal hamster buccal pouch stem/stromal cells – a potential oral cancer stem/stem-like cell model. Oral Oncol 2009;45: e189-e195. 14.Umezawa & Gorham. Dueling models in head and neck tumor formation. Lab Investig 2010; 90:1546-8. 15.Spillane JB, Henderson MA. Cancer stem cells: a review. ANZ J Surg 2007;77:464-8. 16.Zhou ZT, Jiang WW. Cancer stem cell model in oral squamous cell carcinoma. Curr Stem Cell Res Ther 2008;3:17–20. 17.Harper LJ et al. Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma. J Oral Pathol Med 2007;36:594-603. 18.Lim YC et al. Cancer stem cell traits in squamospheres derived from primary head and neck squamous cell carcinomas. Oral Oncol 2011;47:83-91.

3 探索癌症之旅 始 點始 點 How cancer arise Stages of carcinogenesis 癌化的標準教條 四種癌化理論 Field cancerization 癌細胞的六種超能力 癌症的預防 學 習 目 標學 習 目 標 終 點終 點 1 2 3 4 5 6 7

4 In this model, clonal variants, including stromal cells derived from tumor cells, generate a microenvironment (niche) for tumor cells, and support tumor progression after tumor cells undergo clonal evolution. Stochastic Clonal Evolution Model 第一站: How Cancer Arises Ref. 14 Stochastic clonal evolution model Interaction between tumor cells and stromal cells Tumor cell

5 Stem cells create an exact copy of themselves and an EP cell when they divide. The EP cell then progresses to a late progenitor cell and then to the definitive cell line Asymmetrical Division Definitive Tissue Line Early Progenitor Late Progenitor Stem Cell Ref. 15

6 (a) The traditional model of tumor formation. A series of mutations affect a mature cell, causing it to become malignant. Any cell has the potential to form a tumor Traditional Model of Tumor Formation Mature Definitive Tissue Cell Tumor Mutation Mutation Only at the Stem Cell (b) Mutation only at the stem cell or progenitor cell level. The cancer stem cell replicates forming an exact copy of itself as well as a continuous supply of heterogeneous tumor cells Tumor Stem Cell Mutation Ref. 15

7 Cancer Stem Cell Model mutation Self- renewing stem cell Progenitor cell Mature cell Cancer cell Self- renewing cancer stem cell Ref. 15 In the stem cell model, only the stem cells or their progenitor cells have the ability to form tumors. Tumor characteristics vary depending on which cell undergoes the malignant transformation

8 Comparison of Somatic and Cancer Stem Cells Somatic Stem CellCancer Stem Cell Self renew, highly regulatedSelf-renew, poorly regulated Differentiate, produces mature tissue Differentiate, produces tumor Migrate to distant tissuesMetastasize to distant sites Long lifespan Resistant to apoptosis Ref. 15

9 The hierarchical stem cell structure present in human oral epithelia indicates that stem cells are the only long-time residents of oral epithelia and, consequently, the only cells able to accumulate the necessary number of genetic changes for malignancy to develop Stem cell - Oral Epithelia According to the progression model, the development of most of OSCC takes months or years. As normal human oral epithelia have a rate of renewal estimated to be about 14-24 days, most epithelial cells do not exist long enough to accumulate the genetic changes necessary for the development of an OSCC.

10 1, CSC might come from epithelial SC or progenitor within basal layer with genetic alterations; 2, muscle-derived SCs; 3, fibroblast-derived SCs; 4, vessel wall- derived SCs; 5, blood-derived SCs; and 6, adipose derived SCs. A Schematic Diagram Showing Sites of Origins of Putative CSCs in OSCC Epithelium Connective tissue Ref. 16

11 Putative Cell Surface Markers of Presumptive CSC SP-C + CCA + Tumor TypeSurface Markers Ref. 16

12 CD44 + CD24 - Lineage negative CD44 + CD24 - Tumor formed New tumor formed Ref. 16 A minority population of CD44 + cancer cells (<3%/<10% of the cells in head and neck SCC cell line), but not the CD44 - cancer cells, generate new tumors in vivo

13 Potential Mechanisms of CSC Formation CSC MUTATION A Progenitors Self renewal Stem/progenitor cells Differentiated cells Ref. 16

14 CSC MULTIPLE GENETIC HITS B Stem/progenitor cells Potential Mechanisms of CSC Formation Ref. 16

15 CSC FUSION D Cancer cell Stem/progenitor cells Potential Mechanisms of CSC Formation Ref. 16 CSC MULTISTEP DEDIFFERENTIATION C Cancer cell

16 DMBA-Induced Hamster Buccal Pouch Model 14-wk Normal Carcinogen: DMBA Hamster buccal-pouch mucosa provides one of the most widely-accepted experimental models for oral carcinogenesis Ref. 12

17 DMBA-Induced Hamster Buccal Pouch Model Despite anatomical and histological differences between (hamster) pouch mucosa and human buccal tissue, experimental carcinogenesis protocols for the former induce premalignant changes and carcinomas that are similar to the development of premalignancy and malignancy in human oral mucosa. Animal Study Animal Study Human Study Human Study Ref. 12

18 AB Isolation and Characterization of Stem Cells from Normal Hamster Buccal Pouch (HBPSC) Representative sample of the normal hamster buccal pouch tissues revealed no obvious grossly (A; inset) and histological (B, Hematoxylin & eosin stain,  200) changes. Ref. 13

19 Minimal Criteria of Stem Cell Capacity Self-renewal ---Colony forming unit (CFU) ---Proliferation One or more lineages differentiation ---Adipogenic differentiation ---Osteogenic differentiation ---Chondrogenic differentiation ---Neurogenic differentiation

20 Representative sample of the HBPSCs obtained from the normal hamster buccal pouch tissues were spindle-shaped in morphology (  200). Ref. 13

21 A B Representative sample of the HBPSCs obtained from the normal hamster buccal pouch tissues were able to form colonies, stained with crystal violet (A; B,  100). Ref. 13

22 AB Cytoplasmic keratin (A,  200) and vimentin (B,  200) stainings were noted for the representative sample of the HBPSCs obtained from the normal hamster buccal pouch tissues. Ref. 13

23 Proliferation rate (# of folds) Pouch 2Pouch 3 Proliferation rates for the HBPSCs obtained from the three normal hamster buccal pouch tissues (p: passage). Ref. 13

24 A NM GAPDH PPAR  B 50 100 150 200 250 300 350 400 bp (A) Representative sample of the HBPSCs obtained from the normal hamster buccal pouch tissues were able to differentiate towards adipogenic lineage (×200). (B) Expression of PPARγ mRNA (401-bp) upon RT-PCR also indicates adipogenic lineage of HBPSCs obtained from normal hamster buccal pouch tissues; GAPDH (135-bp) was the positive control; H 2 O was the negative control (N); M: molecular weight marker. Ref. 13

25 Representative sample of the HBPSCs obtained from the normal hamster buccal pouch tissues were able to differentiate towards chondrogenic lineage (×200); inset: a yellowish chondroid pellet (~3mm in diameter). Ref. 13 Representative sample of the HBPSCs obtained from the normal hamster buccal pouch tissues were able to differentiate towards osteogenic lineage (×200).

26 Representative sample of the HBPSCs obtained from the normal hamster buccal pouch tissues expressed the differentiation markers (Osteonectin: 323-bp & Nestin: 416-bp) and stem cell markers (Nanog: 364-bp, Rex-1: 232-bp & Oct-4: 717- bp) upon RT-PCR. GAPDH (135-bp) was the positive control; H 2 O was the negative control (N); M: molecular weight marker. MN GAPDH Osteonectin Nestin Oct-4 NanogRex-1 100 200 300 400 500 600 700 bp Ref. 13

27 Representative sample of the HBPSCs obtained from the normal hamster buccal pouch tissues showed high expression for surface markers: CD29, CD90, and CD105 but very low expression for CD14, CD34, and CD45 (Black/blue line: isotype control, Red line: marker of interest; Max: maximum). 0.9 CD14 % of Max 100 CD 29 % of Max 93.6 100 CD 34 % of Max 100 1.7 CD 45 1.5 % of Max 100 CD 90 85.8 % of Max 100 51.3 CD 105 100 % of Max 100 Ref. 13

28 Isolation of normal HBPSC, we may follow in vitro the sequential changes of the normal HBPSCs during multistep oral carcinogenesis or the alternations of these cells upon irradiation treatment and/or chemotherapy. Hence, the isolated normal HBPSCs, would provide a potential avenue for the future study of CSCs of buccal SCCs. DMBA-Induced Hamster Buccal Pouch Model

29 A colony with holoclone characteristics of circular outline and tightly packed cobblestone’ cells (h) is surrounded by cells with a spaced and fusiform paraclone morphology (p). A small colony (m) perhaps corresponds to a meroclone. Comparison of Morphology Between Our Isolated Cells & Literature Results Our isolated cells from DMBA-induced cancer pouch tissue Refs. 13, 17

30 Self-renewal, stem cell marker expression, aberrant differentiation, and tumor-initiating potential OSCC-driven squamospheres demonstrated: (1)A number of stem cell markers, such as CK5, OCT4, SOX2, nestin, and CD44, Bmi-1, CD133, ALDH1 (2) Single-dissociated squamosphere cells were able to form new squamospheres within 1 week of reseeding (3) Serum treatment led HNSCC-driven squamospheres to be non-tumorigenic differentiated cancer cells (4) Injection of as few as 100 undifferentiated squamosphere cells in nude mice gave rise to tumor formation Hallmarks of CSCs (1) CSCs is known to be significantly resistant to various chemotherapeutic agents (cisplatin, 5-fluorouracil (FU), paclitaxel, and doxetaxel)

31 Hallmarks of CSCs (2) Ref. 18

32 Gentically altered cell Hyperlasia Dysplasia Tumor development occurs in stages Genetically altered cell (CSC) Hyperplasia Dysplasia Oral premalignant lesions Leukoplakia, Erythroplakia, Oral submucous fibrosis, Verrucous hyperplasia, Erosive lichen planus 基底層完整 Initiated cell 起始細胞 第二站 : Stages of Carcinogenesis Ref. 1

33 In situ cancer Invasive cancer Blood vessel/ lymphatic vessel Ref. 1 How Cancer Spreads

34 Primary tumor Normal epithelial cell Basement membrane Invasive tumor cell Blood vessel/ lymphatic channel How Cancer Spreads Ref. 1

35 Endothelial/lymphatic lining Basement membrane Metastatic cell in circulation Secondary tumor site Tumor cell adhering to capillary Ref. 1 How Cancer Spreads

36 Initiation Phase (Early) 第二站 : Further look on stages of carcinogenesis 去毒 Ref. 9

37 Initiation Phase (Late) Ref. 9

38 Promotion Phase (Early) Mutant clone establishment & appearance of phenotypically transformed cells Ref. 9

39 Promotion Phase (Late) Establishment of phenotypically transformed cell population (dysplasia) Ref. 9

40 Progression Phase (Early) Malignisation Ref. 9

41 Progression Phase (Middle) Microinvasion Ref. 9

42 Progression Phase (Late) Advanced invasion and metastasis Chemotherapy Ref. 9

43 Normal Cell Cycle Cell enlarges and makes new proteins Beginning of cycle Cell divides (mitosis) Cell prepares to divide Cell replicates as DNA Cell rests Restriction point:cell decides whether to commit itself to the complete cycle 崗 哨崗 哨 第三站 : 癌化理論的標準教條 G1 arrest Ref. 2

44 Inhibitory pathways Normal Cell Inhibitory abnormality Stimulatory abnormality Stimulatory pathways 標準教條 致癌基因抑癌基因 Ref. 2

45 Activation of oncogene Inactivation of tumor suppressor gene Cell Cycle 失 控失 控 失 控失 控 下 坡 煞 車 失 靈 油 門 全 開 Aberrant cell cycle — accelerated cars without brake Ref. 2

46 Oncogene (1) Genes for growth factors or their receptors PDGFCodes for platelet-derived growth factor Involved in glioma (a brain cancer) erb-BCodes for the receptor for epidermal growth factor Involved in glioblastoma (a brain cancer) and breast cancer erb-B2Also called HER-2 or neu. Codes for a growth factor receptor Involved in breast, salivary gland and ovarian cancers RETCodes for a growth factor receptor Involved in thyroid cancer Genes for growth factors or their receptors Ki-rasInvolved in lung, ovarian, colon and pancreatic cancers N-rasInvolved in leukemia Ref. 2

47 Oncogene (2) Genes for growth factors or their receptors c-mycInvolved in leukemia and breast, stomach and lung cancers N-mycInvolved in neuroblastoma (a nerve cell cancer) and glioblastoma L-mycInvolved in lung cancer Genes for growth factors or their receptors Bcl-2Codes for a protein that normally blocks cell suicide. Involved in follicular B cell lymphoma Bcl-1Also called PRAD1. Codes for cyclin D1, a stimulatory component of the cell cycle clock. Involved in breast, head and neck cancers MDM2Codes for an antagonist of the p53 tumor suppressor protein. Involved in sarcomas and other cancers Ref. 2

48 Tumor Suppressor Gene Genes for proteins in the cytoplasm APCInvolved in colon and stomach cancers DPC4Codes for a relay molecule in a signaling pathway that inhibits cell division. Involved in pancreatic cancer NF-1Codes for a protein that inhibits a stimulatory (Ras) protein. Involved in neurofibroma and pheochromocytoma (cancers of the peripheral nervous system) and myeloid leukemia NF-2Involved in meningioma and ependymoma (brain cancers) and schwannoma (affecting the wrapping around peripheral nerves) Ref. 2

49 Tumor Suppressor Gene Genes for proteins whose cellular locations is not yet clear BRCA1Involved in breast and ovarian cancers BRCA2Involved in breast cancer VHLInvolved in renal cell cancer Genes for proteins in the nucleus MTS1Codes for the p16 protein, a braking component of the cell cycle clock. Involved in a wide range of cancers RBCodes for the pRB protein, a master brake of the cell cycle. Involved in retinoblastoma and bone, bladder, small cell lung and breast cancer p53Codes for p53 protein, which can halt cell division and induce abnormal cells to kill themselves. Involved in a wide range of cancers WT1Involved in Wilms’ tumor of the kidney Ref. 2

50 基因突變地圖 在各種癌症中發現超過百種以上的突變基因 癌化理論 → 標準教條: 細胞循環中,正常促進細胞形成基因 o 過度 活化 ,變成致癌基因;而抑制細胞形成基 因 o 發生突變,失去功能 X ,成為抑癌基因 A Subway Map for Cancer Pathways Ref. 2

51 標準教條 第四站 癌化的四個理論 Ref. 2

52 修 正 教 條修 正 教 條 修 正 教 條 在癌化前期的細胞基因組當中, 累積的隨機突變有顯著的增加, 終於影響到癌症相關基因 Ref. 2

53 早期不穩定理論 其餘兩個理論專注 在非整倍體所扮演的 角色,也就是染色體 上大規模的變異 早期不穩定理論 認為細胞分裂的主控基因 受致癌物質影響而關閉, 造成子代細胞染色體數目 異常 Ref. 2

54 全盤非整倍體理論:非整倍體細胞的基因組非常 不穩定,使得癌症基因極易發生突變而形成腫瘤 Ref. 2

55 癌症是一種基因的疾病 然而癌症的複雜情況, 卻不能用簡單的「基因 突變」來描述。 最近理論認為,染色體 的異常可能才是細胞邁 向癌症之路的第一步。 隨染色體起舞 Ref. 2

56 正常癌 症癌 症 Ref. 2 Normal & Cancer Chromosomes

57 Field Cancerization (1) Patch phase Precursor lesions develop within field Carcinoma excised, field and precursor lesion remains Expanding field phase Field Second field tumor develops from precursor lesion Precursor lesions becomes carcinoma and new precursor becomes develop Epithelium Connective tissue Basal layer with stem cells 第五站 : Genetic altered Ref. 7

58 Carcinoma 11q Field Cancerization (2) Field Patch Histological Proof Chromosomal Proof p arm q arm centromere Normal 17p 3p, 9p, 8p, 18q Ref. 8

59 癌細胞的第一種魔鬼能力 第六站 : 癌細胞的六種魔鬼能力 Ref. 2

60 癌細胞的第二種魔鬼能力 第六站 : 癌細胞的六種魔鬼能力 Ref. 2

61 癌細胞的第三種魔鬼能力 第六站 : 癌細胞的六種魔鬼能力 Ref. 2

62 癌細胞的第四種魔鬼能力 第六站 : 癌細胞的六種魔鬼能力 Ref. 2

63 Angiogenesis Factors (1) Tumor island Ref. 3

64 Angiogenesis Factors (2) Newly-formed vessels Tumor cells Normal vessels Ref. 4

65 Angiogenesis Factors (3) Normal epithelium Dysplasia Early localized tumor Advanced invasive tumor Normal vessel Newly-formed vessel Tumor-lined vessel Ref. 4

66 癌細胞的第五種魔鬼能力 第六站 : 癌細胞的六種魔鬼能力 藍 p arm q arm centromere Ref. 2

67 Consequences of teleomere loss in tumor cells Teleomere ( 末端粒腺體 ) Normal Mutant Chromosome instability Chromosome imbalances Gene amplification Teleomere Fusions breakages Duplication of 16q: iso16q Trisomy 16q Monosomy 16q Ref. 10

68 Regulation of Teleomeres – Alterative Length of Teleomere (ALT), Teleomerase or Both GrowthMassive ApoptosisImmortalization Teleomeres shorten Teleomeres are critically short Repeated cell divisions Genomic Instability 3. Teleomerase & ALT ? 2. Telomerase Teleomeres are regulated by 1. ALT Ref. 10

69 Immunohistochemical Staining of Teleomerase Reverse Transcriptase (h-TERT) Brown color stained dots Cancer tissues Ref. 11

70 癌細胞的第六種魔鬼能力 第六站 : 癌細胞的六種魔鬼能力 Ref. 2

71 Causes and Prevention 第七站 What Causes Cancer? Chemical-environment Virus The top two causes - tobacco and diet- account for almost two thirds of all cancer deaths and are amongst most correctable PAPILLOMA VIRUS is a significant cause of cancer Ref. 1

72 Most Oral Carcinoma in Taiwan is Associated with Betel Quid Ref. 12

73 Lancet Oncology 2001; August 印度檳榔包裝 Ref. 6

74 Lancet Oncology 2003; October 印度的檳榔攤 Ref. 5

75 Carcinogens in Work Place (1) 砷 石棉 Ref. 1

76 Carcinogens in Work Place (2) Ref. 1

77 Genes and Cancer Risk 基因警察 DNA 修補基因 Ref. 1

78 Food Strategies for Minimizing Cancer Risk Causes of current cancer mortality Realistic population goals for reduced cancer mortality Risk factors Estimated number of deaths in US (thousands per year) 100,000 to 125,000 current deaths Simple, realistic preventive measures could save hundreds of thousands of lives every year in developed countries alone Realistic Goals for Reducing Cancer Mortality Ref. 1

79 Chemoprevention of Cancer Someday people should be able to avoid cancer or delay its onset by taking specially formulated pills or foods Ref. 1

80 Chemoprevention 的原理 Healthy cell Differentiation cell Genetic mutations that can lead to cancer Processes that lead to excessive proliferation genetically damaged cells Cancer cell Damaged cell (precancer cell) Programmed death of altered cells (Apoptosis) Ref. 1

81 BRCA1 Chromosome 17 A family search for BRCA1 mutation Earlier Detection Advances in Cancer Detection Tests to look for the presence of a tumor before any symptoms appear may save more lives than new drug therapies do Ref. 1

82 Some Family Causing Syndromes SyndromeCancersGene DNA Testing cost Ref. 1

83 Slide is prepared from Humphrey’s urine sample taken in 1967 Section of cancer is taken from Humphrey’s bladder surgically removed in 1967 Copies of DNA are made from PCR Mutant DNA probe Probe bind to mutant DNA Probe for the mutation is constructed DNA is purifed and p53 gene is sequenced Gel shows mutation (red arrow) in p53 gene Normal DNA Mutant DNA DNA is placed on nylon membrane 生物晶片 美國副總統 — 韓福瑞 Diagnosing Hubert H. Humphrey 27 Years Later (2004) Ref. 1 Example of Early Detection

84 Mammograms CT scan Liver Hepatoma Breast Advances in Tumor Imaging Advances in Tumor Imaging New tools yield a three-dimensional view inside the body and automated advice on interpreting the anatomical landscape Ref. 1

85 Advances in Tumor Imaging Advances in Tumor Imaging Positron Emission Tomography Ref. 1

86 Immunotherapy/ Stem Cell Therapy for Cancer Immunotherapy/ Stem Cell Therapy for Cancer Orange: Stroma Green: Colon cancer cell Antibodies recognizes specific cells and can be used to find and selectively destroy tumor cells Ref. 1

87 Fighting Cancer by Attacking Its Blood Supply Inhibition of NOS enzymes by NOS inhibitor Relatively lower level of NO produced by SCC facilitates angiogenesis & tumor dissemination NO NOS inhibitor NO Before therapyAfter therapy NOS inhibitor NOS inhibitor NO: nitric oxideNOS: nitric oxide synthase Ref. 1

88 Summaries 瞭解以下各點: 1. How cancer arise 2. Stages of carcinogenesis 3. 癌化的標準教條 4. 四種癌化理論 5. Field cancerization 6. 癌細胞的六種超能力 7. 癌症的預防

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