[e-mail]

1
?????
Oral Cancer Pathology ??????
????? ?????? ?????
07-31211012755
yukkwa_at_kmu.edu.tw
2
? ? ? ?

1. Gibbs WW. Untangling the roots of cancer. Sci Am
   200328956-65.
2. What you need to know about cancer. Sci Am 1996
   28928-119.
3. Hannen EJM, Riediger D. The quantification of
   angiogenesis in relation to metastasis in oral
   cancer a review. Int. J Oral Maxillofac Surg
   2004332-7.
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 200433601-6.
5. Sharma DC. Betel quid and areca nut are
   carcinogenic without tobacco. Lancet Oncol
   20034587.
6. Sharma DC. Indian betel quid more carcinogenic
   than anticipated. Lancet Oncol 20012464.
7. Braakhuis BJM et al. A genetic progression model
   of oral cancer current evidence and clinical
   implications. J Oral Pathol Med 200433317-22.
8. Braakhuis BJM et al. A Genetic explanation of
   slaughters concept of field cancerization
   evidence and clinical implications. Cancer Res
   2003631727-30.
9. Loktionov A. Common gene polymorphisms, cancer
   progression and prognosis. Cancer Letters
   2004208 1-33.
10. Desmaze C et al. Telomere-driven genomic
    instability in cancer cells. Cancer Letters
    2003194173-82.
11. Hiyama E Hiyama K. Telomerase as tumor marker.
    Cancer Letters 2003194221-33.
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 200945 e189-e195.
14. Umezawa Gorham. Dueling models in head and neck
    tumor formation. Lab Investig 2010 901546-8.
15. Spillane JB, Henderson MA. Cancer stem cells a
    review. ANZ J Surg 200777464-8.
16. Zhou ZT, Jiang WW. Cancer stem cell model in oral
    squamous cell carcinoma. Curr Stem Cell Res Ther
    200831720.
17. Harper LJ et al. Stem cell patterns in cell lines
    derived from head and neck squamous cell
    carcinoma. J Oral Pathol Med 200736594-603.
18. Lim YC et al. Cancer stem cell traits in
    squamospheres derived from primary head and neck
    squamous cell carcinomas. Oral Oncol
    20114783-91.

3
? ? ? ?
??????
Field cancerization
???????
5
3
4
?????????
??????
6
2
Stages of carcinogenesis
?????
7
? ?
1
? ?
How cancer arise
4
???How Cancer Arises
Stochastic Clonal Evolution Model
Ref. 14
5
Cancer 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
Ref. 15
6
Ref. 15
7
Comparison of Somatic and Cancer Stem Cells
Somatic Stem Cell Cancer Stem Cell
Self renew, highly regulated Self-renew, poorly regulated
Differentiate, produces mature tissue Differentiate, produces tumor
Migrate to distant tissues Metastasize to distant sites
Long lifespan Long lifespan
Resistant to apoptosis Resistant to apoptosis
Ref. 15
8
Stem cell - Oral Epithelia

• According to the progression model, the
  development of most oral squamous cell carcinomas
  (OSCCs) take 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.
• 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.

9
A Schematic Diagram Showing Sites of Origins of
Putative Cancer Stem Cells (CSCs) in OSCC
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.
Ref. 16
10
Potential Mechanisms of CSC Formation
Ref. 16
11
Potential Mechanisms of CSC Formation
Ref. 16
12
Potential Mechanisms of CSC Formation
C
Cancer cell
Ref. 16
13
??? Stages of Carcinogenesis
Tumor development occurs in stages
Oral premalignant lesions Leukoplakia,
Erythroplakia, Oral submucous fibrosis, Verrucous
hyperplasia, Erosive lichen planus
Genetically altered cell (CSC)
Hyperplasia
Initiated cell ????
Dysplasia
?????
?????
Ref. 1
14
How Cancer Spreads
Ref. 1
15
Ref. 1
16
How Cancer Spreads
Ref. 1
17
Ref. 9
18
Initiation Phase (Late)
Ref. 9
19
(No Transcript)
20
Ref. 9
21
Ref. 9
22
Ref. 9
23
Ref. 9
24
??? ?????????
Normal Cell Cycle
Beginning of cycle
Cell divides (mitosis)
Cell enlarges and makes new proteins
Cell prepares to divide
Cell rests
G1 arrest
? ?
Restriction point cell decides whether to commit
itself to the complete cycle
Cell replicates as DNA
Ref. 2
25
????
Inhibitor(stop signal)
Growth factor(go signal)
No growthfactor attaches
????
????
Ref. 2
26
Aberrant cell cycle accelerated cars
without brake
? ?
Activation of oncogene
? ?
Inactivation of tumor suppressor gene
Ref. 2
27
Oncogene (1)
Genes for growth factors or their receptors Genes for growth factors or their receptors
PDGF Codes for platelet-derived growth factor Involved in glioma (a brain cancer)
erb-B Codes for the receptor for epidermal growth factor Involved in glioblastoma (a brain cancer) and breast cancer
erb-B2 Also called HER-2 or neu. Codes for a growth factor receptor Involved in breast, salivary gland and ovarian cancers
RET Codes for a growth factor receptor Involved in thyroid cancer
Genes for growth factors or their receptors Genes for growth factors or their receptors
Ki-ras Involved in lung, ovarian, colon and pancreatic cancers
N-ras Involved in leukemia
Ref. 2
28
Oncogene (2)
Genes for growth factors or their receptors Genes for growth factors or their receptors
c-myc Involved in leukemia and breast, stomach and lung cancers
N-myc Involved in neuroblastoma (a nerve cell cancer) and glioblastoma
L-myc Involved in lung cancer
Genes for growth factors or their receptors Genes for growth factors or their receptors
Bcl-2 Codes for a protein that normally blocks cell suicide. Involved in follicular B cell lymphoma
Bcl-1 Also called PRAD1. Codes for cyclin D1, a stimulatory component of the cell cycle clock. Involved in breast, head and neck cancers
MDM2 Codes for an antagonist of the p53 tumor suppressor protein. Involved in sarcomas and other cancers
Ref. 2
29
Tumor Suppressor Gene
Genes for proteins in the cytoplasm Genes for proteins in the cytoplasm
APC Involved in colon and stomach cancers
DPC4 Codes for a relay molecule in a signaling pathway that inhibits cell division. Involved in pancreatic cancer
NF-1 Codes for a protein that inhibits a stimulatory (Ras) protein. Involved in neurofibroma and pheochromocytoma (cancers of the peripheral nervous system) and myeloid leukemia
NF-2 Involved in meningioma and ependymoma (brain cancers) and schwannoma (affecting the wrapping around peripheral nerves)
Ref. 2
30
Tumor Suppressor Gene
Genes for proteins in the nucleus Genes for proteins in the nucleus
MTS1 Codes for the p16 protein, a braking component of the cell cycle clock Involved in a wide range of cancers
RB Codes for the pRB protein, a master brake of the cell cycle. Involved in retinoblastoma and bone, bladder, small cell lung and breast cancer
p53 Codes for p53 protein, which can halt cell division and induce abnormal cells to kill themselves. Involved in a wide range of cancers
WT1 Involved in Wilms tumor of the kidney
Genes for proteins whose cellular locations is not yet clear Genes for proteins whose cellular locations is not yet clear
BRCA1 Involved in breast and ovarian cancers
BRCA2 Involved in breast cancer
VHL Involved in renal cell cancer
Ref. 2
31
??????
Ref. 2
???????????????????
???? ? ???? ?????,??????????o????
,???????????????o????,????X,??????
A Subway Map for Cancer Pathways
32
???
???????
????
???????????????????????,??????????,?????????,??
???
Ref. 2
33
? ? ? ?
Ref. 2
34
???????
Ref. 2
35
???????????????????????,?????????????????
Ref. 2
36
??????
Ref. 2
37
Ref. 2
Normal Cancer Chromosomes
??
? ?
38
???
Field Cancerization (1)
Genetic altered
Expanding field phase
Precursor lesions becomes carcinoma and new
precursor becomes develop
Second field tumor develops from precursor lesion
Ref. 7
39
Field Cancerization (2)
Histological Proof
Chromosomal Proof
Ref. 8
40
??? ??????????
Ref. 2
???????????
41
??? ??????????
Ref. 2
???????????
42
??? ??????????
Ref. 2
???????????
43
??? ??????????
Ref. 2
???????????
44
Angiogenesis Factors (1)
Tumor island
Ref. 3
45
Angiogenesis Factors (2)
Normal vessels
Newly-formed vessels
Tumor cells
Ref. 4
46
Angiogenesis Factors (3)
Ref. 4
47
??? ??????????
Ref. 2
???????????
?
48
Consequences of teleomere loss in tumor cells
Teleomere (?????)
Normal
Teleomere
Mutant
Fusions breakages
Duplication of 16q iso16q Trisomy 16q monosomy
16q
Chromosome instability
Gene amplification
Chromosome imbalances
Ref. 10
49
Regulation of Teleomeres Alterative Length of
Teleomere (ALT), Teleomerase or Both
Growth
Massive Apoptosis
Immortalization
Teleomeres shorten
Teleomeres are critically short
Teleomeres are regulated by
1. ALT
3. Teleomerase ALT ?
Genomic Instability
2. Telomerase
Repeated cell divisions
Ref. 10
50
Immunohistochemical Staining of Teleomerase
Reverse Transcriptase (h-TERT)
Brown color stained dots
Cancer tissues
Ref. 11
51
??? ??????????
Ref. 2
???????????
52
Causes and Prevention
???
Ref. 1
53
Most Oral Carcinoma in Taiwan is Associated with
Betel Quid
Ref. 12
54
Lancet Oncology 2001 August
Indian betel quid more carcinogenic than
anticipated
??????
Ref. 6
55
Lancet Oncology 2003 October
Betel quid and areca nut are carcinogenic
without tobacco
??????
Ref. 5
56
Carcinogens in Work Place (1)
?
??
Ref. 1
57
Carcinogens in Work Place (2)
Ref. 1
58
Genes and Cancer Risk
????
DNA ????
Ref. 1
59
Realistic Goals for Reducing Cancer Mortality
Ref. 1
60
Ref. 1
61
Chemoprevention???
Programmed death of altered cells (Apoptosis)
Ref. 1
62
Ref. 1
63
Some Family Causing Syndromes
DNA Testing cost
Syndrome
Cancers
Gene
Ref. 1
64
Example of Early Detection
Copies of DNA are made from PCR
Slide is prepared from Humphreys urine sample
taken in 1967
Normal DNA
Mutant DNA
????????
Diagnosing Hubert H. Humphrey 27 Years Later
(2004)
DNA is placed on nylon membrane
Mutant DNA probe
Probe bind to mutant DNA
DNA is purifed and p53 gene is sequenced
Probe for the mutation is constructed
Section of cancer is taken from Humphreys
bladder surgically removed in 1967
Gel shows mutation (red arrow) in p53 gene
Ref. 1
65
Ref. 1
66
Advances in Tumor Imaging
Positron Emission Tomography
Ref. 1
67
Immunotherapy/ Stem Cell Therapy for Cancer
Antibodies recognizes specific cells and can be
used to find and selectively destroy tumor cells
Orange Stroma
Green Colon cancer cell
Ref. 1
68
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
NOS inhibitor
NOS inhibitor
NO
NO
NOS inhibitor
Before therapy
After therapy
NO nitric oxide
NOS nitric oxide synthase
Ref. 1
69
Summaries

• ??????
• How cancer arise
• Stages of carcinogenesis
• ???????
• ??????
• Field cancerization
• ?????????
• ?????