Tumor pathogenesis
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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

Tumor pathogenesis

陈玮 副教授

Email:[email protected]

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

Tumor pathogenesis

Tumor pathogenesis

  • Oncogenes

  • Tumor suppressor genes

  • Invasion and Metastasis

Tumor pathogenesis


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


Tumor pathogenesis

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.

Molecular basis of multistep carcinogenesis

Molecular Basis of Multistep Carcinogenesis

Tumor pathogenesis

  • Usually, a single oncogene is not enough to turn a normal cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous.

Tumor pathogenesis


Tumor pathogenesis

Figure 2. 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)




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

  • 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.

Tumor pathogenesis

Classification of proto-oncogenes

  • 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

  • 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




Tumor pathogenesis



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

t(8;22) 15% of cases

t(2;8) 5% of cases

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


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


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

Tumor pathogenesis


OncogeneAmplification Source of tumor

c-myc ~20-foldleukemia and lung carcinoma

N-myc 5-1,000-foldneuroblastoma


L-myc 10-20-foldsmall-cell lung cancer

c-abl ~5-fold chronic myeloid leukemia

c-myb 5-10-foldacute myeloid leukemia

colon carcinoma

c-erbB ~30-foldepidermoid carcinoma

K-ras 4-20-foldcolon carcinoma

30-60-foldadrenocortical carcinoma

Tumor pathogenesis


  • 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.

Tumor pathogenesis

Ras relays signals from the cell surface receptors to the nucleus

Ras relays signals by acting as a switch

Her2 neu erbb 2


  • 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



  • 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


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

Tumor pathogenesis


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 pathogenesis


Disorders in which gene is affected

Gene (locus)Function Familial Sporadic

DCC (18q) cell surface unknowncolorectal

interactions cancer

WT1 (11p) transcription Wilm’s tumorlung cancer

Rb1 (13q) transcription retinoblastomasmall-cell lung


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

syndrome & lung cancer

BRCA1(17q) transcriptionalbreast cancerbreast/ovarian


BRCA2 (13q) regulator/DNA repair

Tumor pathogenesis

Mechanism for the inactivation of TSGs

  • 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

Tumor pathogenesis


Tumor pathogenesis

Rb regulates G1/S transition

Rb inactivation by

viral oncoprotein

Tumor pathogenesis


  • 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

Tumor pathogenesis












Inactivation of a tumor suppressor gene requires two somatic mutations.

Tumor cells

Tumor pathogenesis


  • 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

Tumor pathogenesis



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

Tumor pathogenesis

  • P53 is called the “ guardian of the genome”

  • 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 (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

PTENis 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

  • 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?

  • 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

Invasion and metastasis

Invasion and Metastasis

Stepwise malignant progression of cancer

Stepwise Malignant Progression of Cancer

The process of metastasis consists of sequential linked steps

The process of metastasis consists 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

1.Loss of cell-to cell cohesive forces

2. Secretion of ECM-degrading enzymes

3. Active Locomotion

4. Tumor angiogenesis

5. Metastasis-related genes

Tumor pathogenesis

  • Degradation of ECM by collagenase enzyme

Detachment of tumor cells from each other

Attachments of tumor cells to matrix components

Migration of tumor cells

Tumor pathogenesis

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

Tumor pathogenesis

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

  • 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 (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

Tumor pathogenesis

Mode of cadherin interaction

Tumor pathogenesis

Integrin (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 (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)。

Tumor pathogenesis

IGSF (immunoglobulin superfamily)


Selectin (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)

Tumor pathogenesis


  • 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.

Tumor pathogenesis

  • 2. Secretion of ECM-degrading enzymes

  • 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

Cell invasion of the extracellular matrix

Cell invasion of the extracellular matrix

Mmp matrix metalloproteinases

MMP (matrix metalloproteinases)

  • 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。

Tumor pathogenesis


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¯uPAR-initiated signal transduction and consequences

Plasminogen/Plasmin System

Tumor pathogenesis

  • 3. Active Locomotion

  • 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)

Tumor pathogenesis

4. tumor angiogenesis

  • 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

Tumor pathogenesis

  • How do tumors develop a blood supply?

    • 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 pathogenesis

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

Endogenous angiogenesis inhibitors

Endogenous angiogenesis inhibitors

5 metastasis enhancing genes oncogenes cd44 integrin 1 cea mmp2 u pa etc

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

6 metastasis suppressor genes identified nm23 kai 1 timps e cadherin kiss etc

6. Metastasis-Suppressor Genes Identifiednm23, KAI 1, TIMPs, E-cadherin, Kiss, etc

Modified from JNCI 2000; 92:1717

Metastasis facts

Metastasis Facts

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 pathogenesis

Tumor Microenvironment

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.

Tumor pathogenesis

The diagnosis and therapy of cancer

Tumor pathogenesis

Figure 6. Therapeutic Targeting of the Hallmarks of Cancer.

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).

Tumor pathogenesis

Thank you!

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