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Tumor pathogenesis. 陈玮 副教授 Email : [email protected] 个人主页: http://mypage.zju.edu.cn/566 8888. Tumor pathogenesis Oncogenes Tumor suppressor genes Invasion and Metastasis. Introduction.

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Tumor pathogenesis

陈玮 副教授

Email:[email protected]

个人主页: http://mypage.zju.edu.cn/566 8888


Tumor pathogenesis

  • Oncogenes

  • Tumor suppressor genes

  • Invasion and Metastasis


Introduction

  • Carcinogensis is multistep process involving the multiple genetic changes including the activation of cooperating oncogenes and the inactivation of tumor suppressors in somatic cells

3


Molecular alterations during human

colon tumor progression

(~ 40-50 %)

(~ 60 %)

*

(~ 90 %)

*

(~ 50-70 %)

The precise contribution of hypomethylation to tumor progression remains unclear; some evidence suggests that it creates chromosomal instability.




肿瘤的信号转导通路调控异常 cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.


Figure 2. cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous. Intracellular Signaling Networks Regulate the Operations of the Cancer Cell. An elaborate integrated circuit operates within normal cells and is reprogrammed to regulate hallmark capabilities within cancer cells. Separate subcircuits, depicted here in differently colored fields, are specialized to orchestrate the various capabilities. At one level, this depiction is simplistic, as there is considerable crosstalk between such subcircuits. In addition, because each cancer cell is exposed to a complex mixture of signals from its microenvironment, each of these subcircuits is connected with signals originating from other cells in the tumor microenvironment, as outlined in Figure 5. (Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646)


Oncogene
Oncogene cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.

Concept:

An oncogene is a gene that when mutated or expressed at abnormally-high levels contributes to converting a normal cell into a cancer cell.

  • Cellular oncogene (c-onc):

    --- proto-oncogene (proto-onc):in normal physiologic version

    --- Oncogene:altered in cancer

  • Viral oncogene (v-onc)


Fuctions of proto oncogenes
Fuctions of proto-oncogenes cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.

  • Proto-oncogenes have been identified at all levels of the various signal transduction cascades that control

    cell growth, proliferation and differentiation:

    • extracellular proteins function as growth factors,

    • membrane proteins as cell surface receptors

    • cellular proteins that relay signals

    • proteins innucleus, which activate the transcription and promote the cell cycle

  • This signaling process involves a series of steps that:

    • begin from the extracellular environment to cell membrane;

    • involve a host of intermediaries in the cytoplasm;

    • end in the nucleus with the activation of transcription factors that help to move the cell through its growth cycle.


Classification of proto-oncogenes cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.

  • Growth factors, e.g. V-sis (PDGF), int-2 (FGF)

  • Receptor Tyrosine Kinases,e.g.Her-2/ neu/ erbb2 (EGFR)

  • Membrane Associated Non-Receptor Tyrosine Kinases, e.g.src, Lck

  • Membrane Associated G-Proteins,e.g. Ras

  • Serine/Threonine Kinases e.g. Raf

  • Nuclear DNA-Binding/Transcription Factors, e.g. myc, fos

  • Others

    • Apoptosis regulators, e.g. Bcl-2,

    • Regulators of cell cycle, e.g.Cyclin D1, CDK4


Mechanisms of oncogene activation
Mechanisms of Oncogene Activation cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.

  • Gene amplification, e.g.myc, CCND1

  • Point mutation, e.g.ras,

  • Chromosomal rearrangement or translocation

    • the transcriptional activation of proto-onc.

    • the creation of fusion genes, e.g.abl-bcr

  • Viral insertion activation, e.g.c-Myc


Amplification
Amplification cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.

Translocation


CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.

Neoplasm Translocation Proto-oncogene

Burkitt lymphoma t(8;14) 80% of cases c-myc1

t(8;22) 15% of cases

t(2;8) 5% of cases

Chronic myelogenous t(9;22) 90-95% of cases bcr-abl2

leukemia

Acute lymphocytic t(9;22) 10-15% of cases bcr-abl2

Leukemia

1c-myc is translocated to the IgG locus, which results in its activated expression

2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase


GENE AMPLIFICATION cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.

Oncogene Amplification Source of tumor

c-myc ~20-fold leukemia and lung carcinoma

N-myc 5-1,000-fold neuroblastoma

retinoblastoma

L-myc 10-20-fold small-cell lung cancer

c-abl ~5-fold chronic myeloid leukemia

c-myb 5-10-fold acute myeloid leukemia

colon carcinoma

c-erbB ~30-fold epidermoid carcinoma

K-ras 4-20-fold colon carcinoma

30-60-fold adrenocortical carcinoma


Ras cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.

  • Locates on chromosome 11, codes for a protein with GTPase activity

  • relays signals by acting as a switch:When receptors on the cell surface are stimulated, Ras is switched on and transduces signals that tell the cell to grow. If the cell-surface receptor is not stimulated, Ras is not activated and so the pathway that results in cell growth is not initiated.

  • mutated in about 30% of human cancers so that it is permanently switched on, telling the cell to grow regardless of whether receptors on the cell surface are activated or not.


Ras relays signals from the cell surface receptors to the nucleus

Ras relays signals by acting as a switch


Her2 neu erbb 2
Her2/neu/erbB-2 nucleus

  • This gene was discovered by three different groups. That is why it has three different names.

  • It is a member of EGFR superfamily, also be a receptor tyrosine kinases

  • Dr. Slamon (UCLA) described the role of Her2/neu in breast cancer and ovarian cancer.

  • Overexpression, amplification, rare translocations

  • No ligand is known


Prospect
Prospect nucleus

  • A breakthrough for our understanding of the molecular and genetic basis of cancer

  • Provided important knowledge concerning the regulation of normal cell proliferation, differentiation, and programed cell death.

  • The identification of oncogene abnormalities has provided tools for the molecular diagnosis and monitoring of cancer.

  • Oncogenes represent potential targets for new types of cancer therapies.


Tumor suppressor genes

Tumor suppressor genes nucleus

Concept:

genes that sustain loss-of-function mutations in the development of cancer


TSGs nucleus

Transcriptional factor: p53, WT1,

Direct transcription regulator: Rb, APC

Inhibitor of cell cylcle kinase: p16INK4A, p19ARF,

Cell structural components: NF2

Phosphatase: PTEN

Potential mediator of mRNA processing: VHL

Components involved in DNA repair: MSH2, MLH1, BRCA1, p53


TUMOR SUPPRESSOR GENES nucleus

Disorders in which gene is affected

Gene (locus) Function Familial Sporadic

DCC (18q) cell surface unknown colorectal

interactions cancer

WT1 (11p) transcription Wilm’s tumor lung cancer

Rb1 (13q) transcription retinoblastoma small-cell lung

carcinoma

p53 (17p) transcription Li-Fraumeni breast, colon,

syndrome & lung cancer

BRCA1(17q) transcriptional breast cancer breast/ovarian

tumors

BRCA2 (13q) regulator/DNA repair


Mechanism for the inactivation of TSGs nucleus

  • Mutation: point mutation or frameshift mutation, p53

  • Deletion: LOH (loss of heterozygosity) or homozygous deletion, Rb

  • Viral oncoprotein inactivation: p53, Rb

  • Promoter hypermethylation, histone modification changes: p16


Rb nucleusfunction


Rb regulates G1/S transition nucleus

Rb inactivation by

viral oncoprotein


RB nucleus

  • Retinoblastoma is an uncommon childhood tumor

  • Retinoblastoma is either sporadic (60%) or familial ( 40% )

  • Two mutations required to produce retinoblastoma

  • Both normal copies of the gene should be lost to produce retinoblastoma


RB nucleus

RB

RB

LOH

RB

Mutation

KNUDSON TWO HIT HYPOTHESIS IN SPORADIC CASES

Normal

Cells

RB

RB

Inactivation of a tumor suppressor gene requires two somatic mutations.

Tumor cells


P53: nucleus

  • Common in human cancer 70%

  • Tumor suppressor gene

  • DNA damage – P53 activation by release from MDM2

    • P53 results in arresting the cell cycle by increasing P21.

    • P53 enhance repair of the DNA damage by GADD45

    • P53 induces apoptosis by increasing level of Bax


Bax nucleus

P53

Function as gatekeeper

  • Inactivation of p53 in cancer

  • LOH on 17p13 in a number of tumors

  • Point mutation on exon 5-8 “hot-spot” (Dominant negative mutation)

  • MDM2 negative regulation

  • viral-oncogene products inactivation


  • P53 is called the “ guardian of the genome” nucleus

  • 70% of human cancers have a defect in P53

  • It has been reported with almost all types of cancers : e.g. lung, colon, breast

  • In most cases, mutations are acquired, but can be inhereted, e.g : Li-Fraumeni syndrome


Pten p hosphatase and ten sin homolog
PTEN nucleus (Phosphatase and Tensin Homolog)

  • Pten gene located on Chrom 10 (10q23)

  • PTEN was discovered in 1997 as the first tumor suppressor phosphatase

  • PTEN and PI-3 Kinase act as

    antagonists in lipid signaling


Pten is a lipid 3 phosphatase which signals down the pi3 kinase akt proapoptotic pathway
PTEN nucleusis a lipid 3-phosphatase, which signals down the PI3 kinase/AKT proapoptotic pathway.

Backman et al.


Outcomes of the akt pkb pathway
Outcomes of the Akt/PKB pathway nucleus

  • Role in proliferation complicated

    • PTEN does not merely block proliferation because studies showed that normal bacteria cells expressing PTEN can still undergo rapid proliferation (Liliental et al., 2000)

  • Role in apoptosis more clear

    • Re-expression of PTEN in several carcinoma cell lines induces apoptosis (Li et al, 1998)

    • Especially important is Anoikis, a form of apoptosis that occurs when cells lose contact with the e.c.m. -mediates the cell’s “anchorage dependence” (Davies et al., 1998)


How is pten involved in cancer
How is Pten involved in cancer? nucleus

  • Most frequently mutated gene identified yet in endometrial cancers (33-55% of tumors examined)

  • Of 647 Malignant Glial Tumors examined, 24% showed mutations in PTEN

  • Ovarian tumors (of endometriod origin) showed mutations in 26% of tumors

  • Prostate Carcinoma-mutations in 18% of tumors




The process of metastasis consists of sequential linked steps
The process of metastasis nucleusconsists of sequential linked steps

  • Growth at primary site and angiogenesis

  • Tumor cell invasion

  • Lymphatic and hematogenous metastasis

  • Growth at secondary site and angiogenesis


Mechanisms involved in tumor cell invasion
Mechanisms involved in tumor cell invasion nucleus

1.Loss of cell-to cell cohesive forces

2. Secretion of ECM-degrading enzymes

3. Active Locomotion

4. Tumor angiogenesis

5. Metastasis-related genes


Detachment of tumor cells from each other

Attachments of tumor cells to matrix components

Migration of tumor cells


5. Metastasis-enhancing Genes: nucleusOncogenes,CD44, Integrinβ1, CEA, MMP2, u-PA, etc


  • 1. Loss of cell-to cell cohesive forces: nucleus

  • Cell adhesion molecules (CAMs):

  • 细胞粘附分子:介导细胞之间或细胞与ECM之间的选择性粘附。

  • E-cadherin: Expression↓

  • Loss of cell-cell adhesion,Increased cell motility

  • Integrins: Expression↓→↑

  • Immunoglobin superfamily:NCAM, VCAM-1,CEA, DCC,

  • Selectins

  • CD44 variants


Cadherin
Cadherin nucleus(钙粘素家族)

  • Mediate Ca2+ - dependent homophilic cell-cell adhesion

  • Used in organ formation during development

  • Primarily link epithelial and muscle cells to their neighbors

  • E-cadherins hold epithelial cells together

    expression ↓ in tumor

  • N-cadherins expressed in nervous system are responsible for the specificity of neuronal connections



Integrin nucleus(整合素)

  • Integrin family is so named because the molecules of this family primarily mediate the cellular adherence to extracellular matrix, enabling cells and extracellular matrix to form the integration.


Integrin
Integrin ( nucleus整合素)

1. Structure: Heterodimeric proteins consisting of two non-covalently bound polypeptides ( and  chains).

2. Components of integrin family

1: VLA (very late appearing antigen)

2: LFA-1 (lymphocyte function associated antigen-1); ligand: ICAM-1

3: gpIIb

3. ligands: the component of ECM including fibronectin(纤维黏连蛋白,FN)、vitronectin(玻璃黏连蛋白,VN)、laminin(层黏连蛋白,LM)。



Selectin
Selectin nucleus(选择素)

1. Structure

Transmembrane glycoproteins, with a number of extracellular domains homologous to (CCP). The extracellular region also contains a domain related to the EGF receptor and a distal C type lectin-like domain.

2. Members of selectin family L-selectin: leukocytes P-selectin: platelets and megakaryocytes E-selectin: activated endothelia

3. Ligand: carbohydrates, such as CD15s (sialyl-Lewisx)


CD44 nucleus

  • CD44 is expressed in a large number of mammalian cell types.

  • The standard isoform, designated CD44s, is expressed in most cell types. CD44 splice variants containing variable exons are designated CD44v, which plays a role in tumor metastasis.

  • CD44 is a receptor for hyaluronic acid and can also interact with other ligands, such as osteopontin, collagens, and MMPs.


  • 2. Secretion of ECM-degrading enzymes nucleus

  • Matrix Metalloproteinases (MMPs):~20

  • Tissue inhibitors of metalloproteinases (TIMPs): ~4

  • Plasminogen Activators (PAs) :urokinase-type, tissue-type PA

  • PA inhibitors (PAIs): ~3

Metastasis-associated proteinases



Mmp matrix metalloproteinases
MMP (matrix metalloproteinases) nucleus

  • 间质胶原酶(Interstitial Collagenase ),如MMP-1、MMP-5、MMP-8、 MMP-13等,作用底物主要为间质胶原 Ⅰ、Ⅱ、Ⅲ、Ⅶ、Ⅹ型胶原,但不能降解明胶和Ⅳ型胶原。

  • 明胶酶(Gelatinase )又称Ⅳ型胶原酶,如MMP-2、 MMP- 9,作用底物主要是Ⅳ型胶原和明胶,还可以降解Ⅵ、Ⅶ、Ⅷ和Ⅹ型胶原,但不能降解间质胶原。

  • 基质溶解素(Stromelysin),如MMP-3、 MMP-7、 MMP-10 和MMP-11等,作用底物主要是基质中的蛋白多糖和糖蛋白,如纤维连接蛋白(FN)、层黏连蛋白(LN)等。此外,基质溶解素对胶原的作用不同于间质胶原酶间质和胶原酶,他们能降解Ⅳ、Ⅴ、Ⅷ、Ⅹ型胶原的非螺旋区及Ⅰ型胶原的氨基末端。

  • 膜型金属蛋白酶(Membrane-type MMPs, MT-MMPs ),目前已发现四种,包括MT1-MMP、MT2-MMP、MT3-MMP和MT4-MMP。MT-MMPs主要定位于肿瘤细胞及其基质成纤维细胞的细胞膜上,是MMP的受体,也是MMP的激活剂,还可以降解Ⅰ、Ⅱ、Ⅳ型胶原和FN,其表达受刀豆蛋白、癌基因等因素的调解。


TIMP: nucleus

TIMPs play a key role in maintaining the balance between ECM deposition and its degradation by binding tightly to and regulating MMP actions

Four isoforms: TIMP 1-4


Upa upar initiated signal transduction and consequences
uPA nucleus¯uPAR-initiated signal transduction and consequences

Plasminogen/Plasmin System


  • 3. Active Locomotion nucleus

  • E- cadherin

  • Growth factors and receptors

  • Autocrine motility factor (AMF,自分泌运动分子)

  • Autotaxin (ATX)

  • Cytoskeletal proteins

  • ECM components (LN, etc)


4. tumor angiogenesis nucleus

  • Neovascularization has two main effects:

    • Perfusion supplies oxygen and nutrients

    • Newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors, e.g : PDGF, IL-1

  • Angiogenesis is required for metastasis


  • How do tumors develop a blood supply? nucleus

    • Tumor-associated angiogenic factors

    • These factors may be produced by tumor cells or by inflammatory cells infiltrating the tumor e.g. macrophages

    • Important factors :

      • Vascular endothelial growth factor( VEGF )

      • Fibroblast growth factor (FGF)


Tumor angiogenesis factors (TAFs) nucleus:angiogenin, etc Inhibitors:angiostatin, etc Models of Tumour Angiogenesis



5 metastasis enhancing genes oncogenes cd44 integrin 1 cea mmp2 u pa etc
5. Metastasis-enhancing Genes: nucleusOncogenes, CD44, Integrinβ1, CEA, MMP2, u-PA, etc


6 metastasis suppressor genes identified nm23 kai 1 timps e cadherin kiss etc
6. Metastasis-Suppressor Genes Identified nucleusnm23, KAI 1, TIMPs, E-cadherin, Kiss, etc

Modified from JNCI 2000; 92:1717


Metastasis facts
Metastasis Facts nucleus

Up to 70% of patients with invasive cancer have overt or occult metastases at diagnosis.

Acquisition of the invasive and metastatic phenotype is an early event in cancer progression.

Millions of tumor cells are shed daily into the circulation.

Less than 0.01% of circulating tumor cells successfully initiate a metastatic focus.

Angiogenesis is a ubiquitous and early event that is necessary for and promotes metastatic dissemination.

Invasion and angiogenesis use the same signal transduction programs and gene expression cassettes.

Circulating tumor cells can be detected in patients who do not develop overt metastatic disease.

Metastases may be as susceptible to anti- cancer therapy as their primary tumors?


Tumor Microenvironment nucleus

Figure 4. The Cells of the Tumor Microenvironment.

(Upper) An assemblage of distinct cell types constitutes most solid tumors. Both the parenchyma and stroma of tumors contain distinct cell types and subtypes that collectively enable tumor growth and progression. Notably, the immune inflammatory cells present in tumors can include both tumor-promoting as well as tumor-killing subclasses.

(Lower) The distinctive microenvironments of tumors. The multiple stromal cell types create a succession of tumor

microenvironments that change as tumors invade normal tissue and thereafter seed and colonize distant tissues.

The abundance, histologic organization, and phenotypic characteristics of the stromal cell types, as well as of the

extracellular matrix (hatched background), evolve during progression, thereby enabling primary, invasive, and then metastatic growth.



Figure 6. Therapeutic Targeting of the Hallmarks of Cancer. nucleus

Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use in treating certain forms of human cancer. Additionally, the investigational drugs are being developed to target each of the

enabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs listed are but illustrative examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallmarks.

(Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646).


Thank you! nucleus


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