איבוד בקרת מחזור התא

התא מחזור בקרת איבוד

– " לישראל דומים פופורציונים יחסים ב לארה מתייחסת הסטטיסטיקה

סרטן

גיל של כפונקציה מסרטן תמותה עקומת

MaleFemales

Cancer due to mutations

? סרטן זה מה

טרליון תאים, לכל תא יש את הפוטנציאל להפוך לתא סרטני.20יש בגופנו כ-- ל כללי שם הוא .300סרטן שונות מחלות ויותר

. לכך נדרשים הם כאשר רק מתחלקים הגוף תאי

. אחרות לרקמות הראשוני ממקומם ועוברים בקרה ללא מתחלקים סרטנים תאים

סרטן

" גבוה בקצב ר ועפ בקרה ללא להתחלק שהתחיל אחד מתא מקורו סרטן כל

Cancer Cell 1Cancer cell

? נורמלי תא של ההגדרה מה

- ה את יוצרים מהתא שמופרשים הקולוגן ECMחלבוני

בעיגון מותנה

" מגע י ע עיכוב

גדילה בפקטורי תלות

1

2

3

4

ט ) עבר סרטני תא של ההגדרה אנספורמציה(?רמה

נצח חיי אנפלואידיות

הצורך של מלא או חלקי איבוד . גידול בפקטורי

" מגע י ע גידול עיכוב של איבודל מעוגן להיות הצורך של ECMאיבוד

normal transformed by virus

contact-inhibited pile up, rounded

סרטן שד

התא מחזור בקרת באיבוד מאופנים הסרטן תאי כל

Cell cycle and cancer

גורמות מוטציות סרטן?לאיזה

להתחלק לתא גורמים שלהם שהחלבונים גנים של פעילות מעלות

לא לתא גורמים שלהם שהחלבונים גנים של פעילות מורידותלהתחלק

לסרטן – , הגורמים גנים ויראליים גניםאונקוגנים

התא – בגידול המעורבים לחלבונים המקודדים בתא גנים פרוטואונקוגנים / , ות מוטצי לאחר לאונקוגנים להפוך מסוגלים חלוקתו .או

Sarcoma virus

חלוקתו או התא גידול את חוסמים

תיקון DNAחלבוניעיגון חלבוניגידול מעכבי

What are the genes responsible for tumorigenic cell growth?

Normal

Cancer

Proto-oncogenesCell growth and proliferation

Tumor suppressor genes

+

-

Mutated or “activated”oncogenes

Malignant transformation

Loss or mutation ofTumor suppressor genes

++

- Proto tumor s1up

- - 2Proto to tumor

לחלבונים – המקודדים בתא גנים פרוטואונקוגנים , להפוך מסוגלים חלוקתו או התא בגידול המעורבים

. / ות מוטצי לאחר לאונקוגנים

טרנסלוקציה אמפליפיקציה נקודתית מוטציה

- -Proto tooncogene

Molecular Basis of Philadelphia chromosomeMolecular Basis of Philadelphia chromosome Translocation, causing Translocation, causing chronic chronic myelogenousmyelogenous leukemia leukemia (CML).(CML). Treatment by Gleevec that blokes the abnormal Treatment by Gleevec that blokes the abnormal

enzyme.enzyme.

גליבאק

http://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia



לרטינובלסטומה גורמת העיניים בילדיםמוטציה בשתי

בשלב התא מחזור את G1עוצר- ב אחרים Rbמוטציה בגנים מוטציות להצטברות גורמת

Sarcoma virus

בארבעה 4 נדרשות מוטציות שונים סרטן גנים הגס להופעת המעי

CC

השד סרטן מחולות לחלק גנטי רקע

Hereditary Risk : Genes Affecting DNA repair and Genetic Stability

גורמי סביבה

-5%רק ב מורשות מוטציות נושאות השד סרטן BRCA1 and BRCA2מחולות- ה גנטי 95%ליתר רקע על ידוע לא

סרטן והמערכת האימונית

- - ב או אונקוגנים הפרוטו ממשפחת בגנים tumor sup. Genesמוטציות. לסרטן להוביל יכולה

. " תופיע שהמחלה מ ע אחד בגן ממוטציה יותר נדרשת

ל -BRCA1בגן כ . 200זוהו שד בסרטן לחלות הסיכוי נקודתיות מוטציותלסרטן גורמות כולן ולא למוטציה ממוטציה שונה

סרטן בחולי טיפול דרכי

הקרנותמוטרפיהיכ

ניתוח להסרת הגידול

אנטומיה של בלוטת הפרוסטטה

הפרוסטטה סרטן

Androgen independent prostate cancer

טכניקות ריפוי חדשות שנבדקות במעבדות מחקר

Gene Therapy

Site-Specific Activation of Prodrugs

Retrovirus

Gene expression of virus

RT

ENV

Learning objectives

• understand the concept of “multistep carcinogenesis” and what kindsof genes are mutated during this process

• understand the differences between “oncogenes” and“tumor suppressor genes”

• understand the relationships between viral oncogenes andhost cell oncogenes (proto-oncogenes)

• understand the concept that oncogenes function in signal transduction• understand the mechanisms by which oncogenes are “activated”

during carcinogenesis• understand the concept that tumor suppressor genes are lost or

inactivated during carcinogenesis• understand the concept that a “loss of function” mutation can be

expressed as a dominant disease (Knudson’s two-hit hypothesis)• understand the functions of Rb and p53

Hereditary Risk: Genes Involved in Restraining Cell Proliferation

Hereditary Risk: Genes Affecting DNA Repair and Genetic Stability

Hereditary Risk: Other Genes and Issues

Contents

Chapter 8

Heredity and Cancer

Hereditary Risk: Genes Involved in Restraining Hereditary Risk: Genes Involved in Restraining Cell ProliferationCell Proliferation

► It does not mean that people inherit It does not mean that people inherit cancer from their parentscancer from their parents

►Susceptibility of developing cancerSusceptibility of developing cancer Familial cancersFamilial cancers Hereditary cancersHereditary cancers

►Non-inherited cancerNon-inherited cancer Sporadic cancersSporadic cancers Nonhereditary cancersNonhereditary cancers

Cancer Risk Is Influenced by The Inheritance of Cancer Risk Is Influenced by The Inheritance of Dominant or Recessive Mutation of Varying Dominant or Recessive Mutation of Varying

PenetrancePenetrance

►F 8-1F 8-1►Penetrance: a population of excepted Penetrance: a population of excepted

traittrait

Hereditary Risk : Genes Involved in Restraining Cell Proliferation

Retinoblastoma is a rare childhood cancer of the eye Retinoblastoma is a rare childhood cancer of the eye that occurs in hereditary and nonhereditary formsthat occurs in hereditary and nonhereditary forms

►Light-absorbing retinal cellsLight-absorbing retinal cells►1/20,000 of chance of developing 1/20,000 of chance of developing

retinoblastoma (RB) retinoblastoma (RB) ►Families of retinoblastoma: 50% of Families of retinoblastoma: 50% of

chancechance►F. 8-2F. 8-2►40% RB are familial40% RB are familial►60% are sporadic60% are sporadic


The two-hit model predicts that two mutations needed The two-hit model predicts that two mutations needed to trigger the development of retinoblastomato trigger the development of retinoblastoma

► Mechanism: in 1971, two-hit modelMechanism: in 1971, two-hit model► F. 8-3F. 8-3► Deletion region located on chromosome 13Deletion region located on chromosome 13

Association with both the hereditary and Association with both the hereditary and nonhereditary form of RBnonhereditary form of RB

RBRB gene gene► Both alleles must be mutant (or deleted) for Both alleles must be mutant (or deleted) for

cancer developmentcancer development► But the penetrance of retinoblastoma in But the penetrance of retinoblastoma in

children who inherit a single defective RB children who inherit a single defective RB gene is gene is 90%90%

►


The RB gene is a suppressor of cell proliferationThe RB gene is a suppressor of cell proliferation

►RB proteinRB protein►Tumor suppressor geneTumor suppressor gene

Familial Adenomatosis Polyposis is a colon cancer Familial Adenomatosis Polyposis is a colon cancer syndrome caused by inherited mutations in the APC syndrome caused by inherited mutations in the APC

genegene► 5% colon cancer cases are inherited-mutation 5% colon cancer cases are inherited-mutation

(7500/year in USA)(7500/year in USA)► F. 8-4F. 8-4► At least one of the polyps is likely to turn malignant At least one of the polyps is likely to turn malignant

by the time of 40 y/oby the time of 40 y/o► APCAPC gene is responsible for familial adenomatous gene is responsible for familial adenomatous

polyposis (a tumor suppressor gene)polyposis (a tumor suppressor gene)► APC protein can inhibit the Wnt signaling pathwayAPC protein can inhibit the Wnt signaling pathway► Wnt signaling pathway palys a prominent role in Wnt signaling pathway palys a prominent role in

regulating cell proliferation and differentiation in regulating cell proliferation and differentiation in embryonic developmentembryonic development

► Loss of functional APC protein: enhancing cell Loss of functional APC protein: enhancing cell proliferationproliferation

► F. 10-8 F. 10-8


The Li-Fraumeni Syndrome is caused by inherited The Li-Fraumeni Syndrome is caused by inherited defects in the p53 genedefects in the p53 gene

►Li-Fraumeni SyndromeLi-Fraumeni Syndrome►F. 8-5F. 8-5►Li-Fraumeni Syndrome confers 90% of Li-Fraumeni Syndrome confers 90% of

developing cancer but no single cancer developing cancer but no single cancer predominantspredominants

►Osteosarcomas, breast cancers, Osteosarcomas, breast cancers, leukemia's, adrenal carcinomas, brain leukemia's, adrenal carcinomas, brain tumors……tumors……

►Defection of Defection of p53p53 gene (a tumor gene (a tumor suppressor gene)suppressor gene)

►F. 10-5 F. 10-5


Hereditary cancer syndromes arising from defects Hereditary cancer syndromes arising from defects in genes that restrain cell proliferation share in genes that restrain cell proliferation share

several features in commonseveral features in common►Common featuresCommon features

By a single tumor suppressor geneBy a single tumor suppressor gene A dominant traitA dominant trait Two-fit modelTwo-fit model 50% chance of inheriting the gene defect50% chance of inheriting the gene defect Inactivation or loss of tumor suppressor Inactivation or loss of tumor suppressor

genegene Have non-hereditary cancersHave non-hereditary cancers

►Other tumor suppressor genes (T. 8-1)Other tumor suppressor genes (T. 8-1)


Hereditary Risk: genes affecting DNA Hereditary Risk: genes affecting DNA repair and genetic stabilityrepair and genetic stability

►GatekeepersGatekeepers►CaretakersCaretakers

Xeroderma pigmentosum is an inherited sensitivity Xeroderma pigmentosum is an inherited sensitivity to sunlight-induced skin cancerto sunlight-induced skin cancer

► Xeroderma pigmentosum is a first report of Xeroderma pigmentosum is a first report of DNA repair and cancerDNA repair and cancer

► Sensitive to UV radiationSensitive to UV radiation► F. 8-6F. 8-6► Involving two mutant copies of the same Involving two mutant copies of the same

gene inherited from mother and fathergene inherited from mother and father► A recessive traitA recessive trait► F. 8-7F. 8-7► F. 8-8F. 8-8




Xeroderma pigmentosum is caused by inherited Xeroderma pigmentosum is caused by inherited defects in excision repairdefects in excision repair

►Mutations in seven different genes about Mutations in seven different genes about excision repairexcision repair Code for enzymes for excision repair Code for enzymes for excision repair

pathwaypathway Inheriting two defective copies of any one of Inheriting two defective copies of any one of

these seven genes halts excision repair and these seven genes halts excision repair and creates the cancer predisposition syndromecreates the cancer predisposition syndrome

►XPVXPV gene, the eighth gene, is a gene for gene, the eighth gene, is a gene for DNA polymerase eta which catalyzes DNA polymerase eta which catalyzes translesion stnthesistranslesion stnthesis

Hereditary Nonpolyposis Colon Cancer (HNPCC) Hereditary Nonpolyposis Colon Cancer (HNPCC) is caused by inherited defects in mismatch repairis caused by inherited defects in mismatch repair

►At least 8 repair genes involving At least 8 repair genes involving (~75%)(~75%)

Mutations is the BRCA1 and BRAC2 genes are linked Mutations is the BRCA1 and BRAC2 genes are linked to inherited risk for breast and ovarian cancerto inherited risk for breast and ovarian cancer

► 1/8 women in USA will develop breast 1/8 women in USA will develop breast cancercancer

► 10% breast cancer cases are hereditary10% breast cancer cases are hereditary► Mutation (or defection) either the Mutation (or defection) either the BRCA1BRCA1 or or BRCA2BRCA2 gene gene

► F. 8-9F. 8-9► Non-genetic factors also significantly affect Non-genetic factors also significantly affect

the risk of developing breast cancerthe risk of developing breast cancer► BRAC1 and 2 genes are involved in DNA BRAC1 and 2 genes are involved in DNA

repairrepair


Inherited defects in DNA repair underlie ataxia Inherited defects in DNA repair underlie ataxia telangiectasia, Bloom syndrome, and Fanconi telangiectasia, Bloom syndrome, and Fanconi

Anemia Anemia ►ATM gene code a protein involved in ATM gene code a protein involved in

the DNA damage responsethe DNA damage response For detecting of DNA damage (especially For detecting of DNA damage (especially

ds DNA break)ds DNA break) F. 10-5 and 10-13F. 10-5 and 10-13

►BLMBLM gene code for DNA helicase gene code for DNA helicase►Fanconi anemia is a recessive pattern Fanconi anemia is a recessive pattern

of inheritanceof inheritance Mutation of at least one of 11 genes which Mutation of at least one of 11 genes which

involved in DNA damage responsible involved in DNA damage responsible pathwaypathway

Hereditary Risk: other genes and Hereditary Risk: other genes and issuesissues

Multiple endocrine neoplasia type II is caused by Multiple endocrine neoplasia type II is caused by an inherited mutation in a proto-oncogenean inherited mutation in a proto-oncogene

►Multiple endocrine neoplasia type II is Multiple endocrine neoplasia type II is caused by a mutant caused by a mutant RETRET gene which gene which codes for Ret receptor protein (binding codes for Ret receptor protein (binding with GF)with GF)

►Mutant RET gene produces a Mutant RET gene produces a constitutively active Ret receptorconstitutively active Ret receptor

►Gain-of-function mutationGain-of-function mutation►An oncogeneAn oncogene►F. 8-10F. 8-10

Hereditary Risk : Other Genes and Issues

Inherited variations in immune function and Inherited variations in immune function and metabolic enzymes can influence cancer riskmetabolic enzymes can influence cancer risk

►Primary immunodeficiency diseasePrimary immunodeficiency disease Caused by inherited mutationCaused by inherited mutation Immune system dysfunction Immune system dysfunction Associated with Lymphoma (often by EBV Associated with Lymphoma (often by EBV

infection)infection)

► Inhereditary mutation on liver Inhereditary mutation on liver enzymes or proteinsenzymes or proteins Cytochrome P450 enzymesCytochrome P450 enzymes

Cancer susceptibility is influenced by inheritance Cancer susceptibility is influenced by inheritance of small-risk as well as high-risk genesof small-risk as well as high-risk genes

►Small-risk genes affect cancer Small-risk genes affect cancer susceptibility can be significantsusceptibility can be significant Difficult to identifyDifficult to identify Not for cancer inheritanceNot for cancer inheritance

►F. 8-11F. 8-11


Genetic testing for cancer predisposition has Genetic testing for cancer predisposition has benefits as well as risksbenefits as well as risks

►A cancer is likely to be hereditary?A cancer is likely to be hereditary? Without an obvious environmental or Without an obvious environmental or

lifestyle explanation (such as smoking)lifestyle explanation (such as smoking) Developing cancer during childhood or Developing cancer during childhood or

earlier than typicalearlier than typical Developing multiple cancers or different Developing multiple cancers or different

types of cancer in successiontypes of cancer in succession

►Genetic testingGenetic testing►T. 8-2T. 8-2


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איבוד בקרת מחזור התא