浙江大学：肿瘤发病机制（PPT讲稿）Tumor pathogenesis

Tumor pathogenesis 陈玮副教授 Email:chenwei566@zju.edu.cn 个人主页http:/mypage.zju.edu.cn/5668888

1 Tumor pathogenesis 陈玮 副教授 Email：chenwei566@zju.edu.cn 个人主页： http://mypage.zju.edu.cn/566 8888

Tumor pathogenesis ◆ Oncogenes Tumor suppressor genes Invasion and metastasis

Tumor pathogenesis ◆ Oncogenes ◆ Tumor suppressor genes ◆ Invasion and Metastasis

Introduction a Carcinogensis is multistep process involving the multiple genetic changes including the activation of cooperating oncogenes and the inactivation of tumor suppressors in somatic cells Initiation Promotion Conversion Progression Defects in Terminal Differentiation Defects in Growth Control Resistance to Cytotoxicity Defects in Programmed Cell Death D =)A oNvRUs NORMAL CELL NITIATED ENEOPLASTIC CLINICAL CANCER CELL LESION CANCER METASTASIS Activation of Proto-Oncogenes e Inactivation of Tumor Suppressor Genes Inactivation of Antimetastasis Genes Cancer Susceptibility Genes

3 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

Molecular alterations during human colon tumor progression DNA(~40-50%) hypomethylation (~60%) (~90%) activation loss of loss of Apc of K-ras 18q TSG loss of p53w50-70 % normal _hyperplastic early+intermediate +late i carcinoma invasion epithelium epithelium adenomas metastasis The precise contribution of hypomethylation to tumor progression remains unclear some evidence suggests that it creates chromosomal instability

Molecular alterations during human colon tumor progression The precise contribution of hypomethylation to tumor progression remains unclear; some evidence suggests that it creates chromosomal instability. (~ 90 %) (~ 40-50 %) (~ 50-70 %) (~ 60 %) * *

Molecular Basis of Multistep Carcinogenesis NORMAL COLONIC EPITHELIUM Homozygous loss of APC locus on 5q Mutation of ras on 12p Cells proliferate and form an adenoma Homozygous loss of DCC on 18q More proliferation, larger adenoma cells look abnormal Homozygous loss of p53 on 17p INVASIVE CARCINOMA

Molecular Basis of Multistep Carcinogenesis

a 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 Ras Anchorage independent No tumor Myc Immortal No tumor Ras \Myc Anchorage- independent Tumor and immortal formation FIGURE 7-12 Synergy between oncogenes may be necessary to initiate malignant growth. A, The ras gene only. B, The myc gene only C, Synergy between ras and myc genes

 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

Survival Factors Growth Factors (e.g. IGF1) (e.g. interleukins, (e.g. TGFa, EGF) Extracellular Matri GPCR RTK RTK cdc42 PLC Grb2/sOs Fyn/Shc Dishevelled Src PKC Adenylate GSK-3B Akker MEK Hedgehog IKB MKK B-catenin (e.g, EPC) JAKs STAT5 Myc: -Ma Bcl-xL Max-Max ERK JNKs B-catenin: TCF Cytochrome C CyclO RbYCDK4 p15 Caspase 8 Apoptosis cycE←p27 ARF CDK2 Cel FADD mdm2 Bcl-2 ,ps3 (Proliferation mads (e.g. FasL, Tnf

肿瘤的信号转导通路调控异常

Motility Circuits Cytostasis and Differentiation Circuits ti-growth adjacent cells -+ E-cadherin e b-catenin TCF4- p16 extracellular-+integrins -O-O+O 0 Smads matrix Proliferation Circuits ↓99十 growth Ras→>0→ →O+chan DNA-damage in gene Hallmark senso -expression apabilities hormones→ ○-0 survival factors ○→0→0-0 abnormality factors sensor cvtokines Viability Circuits 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 such subcircuits 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)

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)

Oncogene 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 a Cellular oncogene(c-onc) proto-oncogene( proto-onc): in normal physiologic version Oncogene altered in cancer 口 iral oncogene(-onc

Oncogene 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 r Proto-oncogenes have been identified at all levels of the various signal transduction cascades that control cell growth, proliferation and differentiation: e extracellular proteins function as growth factors o membrane proteins as cell surface receptors o cellular proteins that relay signals proteins in__nucleus, which activate the transcription and promote the cell cycle This signaling process involves a series of steps that o begin from the extracellular environment to cell membrane o 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 cvcle

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 in nucleus, 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. Fuctions of proto-oncogenes