惡性腫瘤的分子生物學(xué)課件

1、惡性腫瘤的分子生物學(xué)惡性腫瘤的分子生物學(xué)惡性腫瘤的分子生物學(xué)惡性腫瘤的分子生物學(xué)圖1 卵巢腫瘤A：GAe組雛雞接種MDV GA株后40天，卵巢形成明顯腫瘤（如箭頭所示）；B：GA0組卵巢正常（如箭頭所示）；C：異常卵巢和正常卵巢的直觀比較） 圖2 睪丸腫瘤A：GA0組睪丸正常（如箭頭所示）；B：GAe組雛雞接種MDV GA株后40天，睪丸形成明顯腫瘤（如箭頭所示）； C：異常睪丸和正常睪丸的直觀比較） 圖1 卵巢腫瘤圖2 睪丸腫瘤惡性腫瘤的分子生物學(xué)課件腫瘤(tumor) 是機(jī)體在各種致瘤因素作用下，局部組織的細(xì)胞在基因水平上失去對(duì)其生長(zhǎng)的正常調(diào)控，導(dǎo)致克隆性異常增生而形成的新生物9.1 概述

2、腫瘤(tumor)9.1 概述腫瘤有良性、惡性之分。僅快速增殖而不擴(kuò)散的稱為良性腫瘤；而不僅異?？焖僭鲋常壹?xì)胞可發(fā)生擴(kuò)散轉(zhuǎn)移的稱為惡性腫瘤，特稱為癌（cancer）或新生物（neoplasm）。癌的主要特征：不受機(jī)體整體的制約，“為所欲為”地快速增殖。 除了侵占正常細(xì)胞所占的空間外，還發(fā)生擴(kuò)散和轉(zhuǎn)移，形成新的病灶。腫瘤有良性、惡性之分。僅快速增殖而不擴(kuò)散的稱為良性腫瘤；而不Benign tumors arise with great frequency but pose little risk because they are localized and smallBenign tumor

3、s arise with greatMalignant tumors generally invade surrounding tissue and spread throughout the bodyAlterations in cell-cell interactions and the formation of new blood vessels are associated with malignancyMalignant tumors generally inv惡性腫瘤的轉(zhuǎn)移惡性腫瘤的轉(zhuǎn)移對(duì)腫瘤發(fā)生的分子機(jī)制，最初人們認(rèn)為是病毒瘤基因所致；70年代中期，畢曉普和瓦慕斯發(fā)現(xiàn)動(dòng)物正常細(xì)胞

4、中本來存在癌基因（原癌基因）；正常情況下，瘤基因?qū)?xì)胞的生長(zhǎng)、分化、調(diào)節(jié)和維護(hù)正常功能起重要作用；近來發(fā)現(xiàn)細(xì)胞中有抑制腫瘤發(fā)生的抑瘤基因。1989年諾貝爾生理學(xué)或醫(yī)學(xué)獎(jiǎng) 分子腫瘤學(xué)認(rèn)為惡性腫瘤是一種涉及基因改變的疾病對(duì)腫瘤發(fā)生的分子機(jī)制，最初人們認(rèn)為是病毒瘤基因所致；1989For cancer: two classes of cellular genes are targets for mutationsPROTO-ONCOGENESTUMOUR SUPRESSOR GENESThe vast majority of these mutations are somaticFor cancer

5、: two classes of celBalance of Tissue Cell NumberBalance of Tissue Cell Number惡性腫瘤的分子生物學(xué)課件 Oncogenes(癌基因)Normal genes (regulate cell growth)1st mutation(leads to accelerated cell division)1 mutation sufficient for role in cancer development ExampleOncogenes derived from growth factor receptors confe

6、r the ability to bypass the growth factor requirementleading to independent growth. Oncogenes(癌基因)Normal genes (rTumour suppressor genes（腫瘤抑制基因）Act as a brake for cell division“GUARDIAN OF THE GENOME”PROBLEM:Mutation in tumour suppressor genes = brakes dont work, or there is an accumulations of muta

7、tions (DNA repair enzymes)The mutated gene product is not functional = NULL ALLELETumour suppressor genes（腫瘤抑制基因Inactivated tumour suppressor gene腫瘤發(fā)生Activated proto-oncogeneInactivated tumour suppressor Effector cytotoxic T lymphocytes (CTLs) attach to these molecules and are nonspecifically recrui

8、ted from the bloodstream into non-lymphoid tissues.例如：膀胱癌EJ株C-Ha-ras基因外顯子12密碼子的突變4 抑癌基因的作用及其致癌機(jī)制外源性抗原經(jīng)APC攝取后，在溶酶體中降解為短肽，由MHC類分子提呈給CD4+T細(xì)胞；Dendritic cells (DCs) take up antigen by distinct endocytosis mechanisms and present it to CD4+ T helper (TH) cells through MHC class II molecules and cross-prese

9、nt it to CD8+ cytotoxic T lymphocytes (CTLs) through MHC class I molecules.近來發(fā)現(xiàn)細(xì)胞中有抑制腫瘤發(fā)生的抑瘤基因。DC需要經(jīng)歷由不成熟向成熟階段的轉(zhuǎn)變才能有效刺激T細(xì)胞活化。例如：膀胱癌EJ株C-Ha-ras基因外顯子12密碼子的突變Chemokine-mediated regulation of cross-priming is illustrated.c-MYC over-expressed in colon cancer此外，DC還通過延伸其樹突狀突起，增加與T細(xì)胞相互作用的機(jī)會(huì)。the t(9;22)(q34;

10、q11) reciprocal translocationHelpless CTLs activated by unlicensed DCs die following secondary encounter with antigen in their effector phaseAPC (腺瘤樣結(jié)腸息肉)RET - MEN 2a對(duì)腫瘤發(fā)生的分子機(jī)制，最初人們認(rèn)為是病毒瘤基因所致；A：GA0組睪丸正常（如箭頭所示）；是機(jī)體在各種致瘤因素作用下，局部組織的細(xì)胞在基因水平上失去對(duì)其生長(zhǎng)的正常調(diào)控，導(dǎo)致克隆性異常增生而形成的新生物分子腫瘤學(xué)認(rèn)為惡性腫瘤是一種涉及基因改變的疾病3 癌基因致癌的分子機(jī)制

11、癌基因(oncogeny，onc) 是指能導(dǎo)致細(xì)胞惡性轉(zhuǎn)化的核酸片段。主要包括病毒癌基因、細(xì)胞癌基因 以及與細(xì)胞生長(zhǎng)因子及其受體、蛋白激酶、轉(zhuǎn)錄因子及其信息加工、傳遞等有關(guān)的基因。9.2 幾個(gè)基本概念Effector cytotoxic T lymphocyt病毒癌基因（virus oncogenes, V-onc）：存在于病毒基因組內(nèi)的癌基因，病毒感染動(dòng)物時(shí)，可誘導(dǎo)動(dòng)物體內(nèi)腫瘤形成。DNA病毒RNA病毒（反轉(zhuǎn)錄病毒）細(xì)胞癌基因（cellular oncogenes,C-onc）：存在于動(dòng)物細(xì)胞中的癌基因。正常情況下主要在胚胎期表達(dá)，在出生后的個(gè)體內(nèi)不表達(dá)或限量表達(dá)，主要功能是促進(jìn)細(xì)胞的正常增

12、殖和分化，又稱原癌基因，被致癌因素激活時(shí)，可誘導(dǎo)細(xì)胞癌變。病毒癌基因（virus oncogenes, V-onc）：抑癌基因（tumorsuppressor gene，TSG） 又稱抗癌基因（anti-oncogene）、隱性癌基因（recessive oncogene），是正常細(xì)胞中存在的對(duì)原癌基因表達(dá)功能進(jìn)行調(diào)節(jié)的基因，可抑制細(xì)胞生長(zhǎng)并能潛在抑制癌變。它的失活或突變具有促進(jìn)腫瘤生長(zhǎng)的潛勢(shì)。抑癌基因活性的下降(功能缺失突變)也可引起癌癥的發(fā)生。抑癌基因（tumorsuppressor gene，TSG）含轉(zhuǎn)錄啟動(dòng)子 LTR gag pol env src LTR 長(zhǎng)末端重復(fù)序列癌基因正常的

13、病毒基因 產(chǎn)生病毒表面糖蛋白產(chǎn)生逆轉(zhuǎn)錄酶和整合酶 產(chǎn)生病毒 垮膜蛋白產(chǎn)生p60src蛋白質(zhì)，磷酸化蛋白。靶蛋白磷酸化Rous于1910年首先發(fā)現(xiàn)雞肉瘤病毒（后稱勞斯肉瘤病毒RSV）1966 諾貝爾獎(jiǎng)9.3 癌基因致癌的分子機(jī)制病毒癌基因含轉(zhuǎn)錄啟動(dòng)子 LTR gag pol env 縱向傳播：原病毒隨細(xì)胞分裂傳遞橫向傳播：原病毒轉(zhuǎn)錄表達(dá)（參與癌癥的發(fā)生）縱向傳播：原病毒隨細(xì)胞分裂傳遞原癌基因致癌的分子機(jī)制有時(shí)原癌基因中一個(gè)核苷酸的突變會(huì)使基因表達(dá)異常的蛋白產(chǎn)物，從而使細(xì)胞向惡性轉(zhuǎn)化。例如：膀胱癌EJ株C-Ha-ras基因外顯子12密碼子的突變基因點(diǎn)突變?cè)┗蛑掳┑姆肿訖C(jī)制有時(shí)原癌基因中一個(gè)核苷

14、酸的突變會(huì)使基因基因擴(kuò)增蛋白質(zhì)結(jié)構(gòu)未變化，但總量大大提高基因擴(kuò)增 原癌基因基因在細(xì)胞中拷貝數(shù)增加，從而使可用的轉(zhuǎn)錄模板數(shù)大大增加?；驍U(kuò)增蛋白質(zhì)結(jié)構(gòu)未變化，但總量大大提高基因擴(kuò)增 原癌基因基染色體易位或重排慢性粒細(xì)胞白血癥(Chronic myeloid leukaemia，CML) is characterised bythe t(9;22)(q34;q11) reciprocal translocation染色體易位或重排慢性粒細(xì)胞白血癥(Chronic myelo病毒啟動(dòng)子插入病毒啟動(dòng)子插入基因間相互作用 腫瘤細(xì)胞中常常不是由一種C-onc表達(dá)異常，有時(shí)需幾種C-onc發(fā)生改變，產(chǎn)生協(xié)同

15、作用方可奏效 基因間相互作用 腫瘤細(xì)胞中常常不是由一種C-onc表達(dá)異正常情況下這兩類信號(hào)保持著動(dòng)態(tài)平衡，十分精確地調(diào)控細(xì)胞增殖和成熟。70年代中期，畢曉普和瓦慕斯發(fā)現(xiàn)動(dòng)物正常細(xì)胞中本來存在癌基因（原癌基因）；它的失活或突變具有促進(jìn)腫瘤生長(zhǎng)的潛勢(shì)。Oncogenes(癌基因)基因在細(xì)胞中拷貝數(shù)增加，從而使可用的轉(zhuǎn)錄模板數(shù)大大增加。C：異常睪丸和正常睪丸的直觀比較）Rous于1910年首先發(fā)現(xiàn)雞肉瘤病毒（后稱勞斯肉瘤病毒RSV）Loss of both copiesBenign tumors arise with great frequency but pose little risk beca

16、use they are localized and small正向調(diào)控信號(hào)：主要是起促進(jìn)細(xì)胞生長(zhǎng)和增殖，并且阻止其發(fā)生終末化傾向，癌基因起著這方面的作用。守門基因（gatekeeper gene）是指在細(xì)胞惡性轉(zhuǎn)化過程中與癌基因啟動(dòng)相關(guān)的基因。Tumour suppressor genes（腫瘤抑制基因）Recruitment of cross-primed effector cytotoxic T lymphocytes into non-lymphoid tissues.惡性腫瘤細(xì)胞在生物學(xué)研究中的應(yīng)用正常情況下這兩類信號(hào)保持著動(dòng)態(tài)平衡，十分精確地調(diào)控細(xì)胞增殖和成熟。RB1 - reti

17、noblastoma susceptibility gene守門基因（gatekeeper gene）是指在細(xì)胞惡性轉(zhuǎn)化過程中與癌基因啟動(dòng)相關(guān)的基因。Chemokine-mediated regulation of cross-priming is illustrated.腫瘤有良性、惡性之分。借助交叉遞呈機(jī)制，APC可以主動(dòng)攝取病毒蛋白或腫瘤抗原，并通過MHC類分子將抗原呈遞給CD8+T細(xì)胞，從而產(chǎn)生有效的CTL應(yīng)答，達(dá)到清除靶細(xì)胞的目的。 正常細(xì)胞的基因，具有相對(duì)穩(wěn)定的甲基化類型，特別是原癌基因的甲基化可使其難以表達(dá)。 原癌基因甲基化水平降低正常情況下這兩類信號(hào)保持著動(dòng)態(tài)平衡，十分精確地調(diào)

18、控細(xì)胞增殖和Examples of OncogenesRAS - activated in many cancers (colon)c-MYC over-expressed in colon cancer(amplified in lung, rearranged in lymphoma)RET - MEN 2aMET - hereditary papillary renal cancerCDK4 - familial melanomaBCR/ABL - chronic myelogenic leukaemiaBCL2 - follicular lymphomaExamples of Onco

19、genesRAS - act9.4 抑癌基因的作用及其致癌機(jī)制抑癌基因在染色體中起穩(wěn)定性作用；參與細(xì)胞分化以控制腫瘤形成，細(xì)胞的終末 分化可抑制細(xì)胞分裂；參與衰老過程，誘導(dǎo)細(xì)胞程序性死亡；通過調(diào)控細(xì)胞周期，調(diào)節(jié)細(xì)胞增殖。正常情況下抑癌基因的作用：抑癌作用通過抑瘤基因表達(dá)“抑癌蛋白”實(shí)現(xiàn)9.4 抑癌基因的作用及其致癌機(jī)制正常情況下抑癌基因的作用：抑癌基因改變的分子基礎(chǔ)錯(cuò)配修復(fù)基因缺陷 抑癌基因改變的分子基礎(chǔ)錯(cuò)配修復(fù)基因缺陷 守門基因和看護(hù)基因的突變失活 守門基因（gatekeeper gene）是指在細(xì)胞惡性轉(zhuǎn)化過程中與癌基因啟動(dòng)相關(guān)的基因。 看護(hù)基因（caretaker，gene）是指保持細(xì)胞

20、基因組穩(wěn)定性，而與細(xì)胞惡性轉(zhuǎn)化過程中癌基因的啟動(dòng)不直接相關(guān)的基因。守門基因和看護(hù)基因的突變失活 守門基因（gatekeeGenetic Control of Neoplastic Initiation and PromotionGatekeeper genesCaretaker genesGenetic Control of Neoplastic Examples of tumour suppressor genes includeRB1 - retinoblastoma susceptibility gene WT1 - Wilms tumour gene NF1 - neurofibrom

21、atosis type 1 gene NF2 - neurofibromatosis type 2 gene DCC - involved in colorectal cancer BRCA1, BRCA2 - involved in breast cancerExamples of tumour suppressor Today we will look at these tumour suppressor genes:Rb (視網(wǎng)膜母細(xì)胞瘤)p53APC (腺瘤樣結(jié)腸息肉)Today we will look at these tu惡性腫瘤的分子生物學(xué)課件Knudsons “Two-Hit

22、” Model for RetinoblastomaNormal 2 intact copiesPredisposed 1 intact copy1 mutationAffected Loss of both copiesKnudsons “Two-Hit” Model forA：GA0組睪丸正常（如箭頭所示）；70年代中期，畢曉普和瓦慕斯發(fā)現(xiàn)動(dòng)物正常細(xì)胞中本來存在癌基因（原癌基因）；Gatekeeper genes抑癌基因（tumorsuppressor gene，TSG）它的失活或突變具有促進(jìn)腫瘤生長(zhǎng)的潛勢(shì)。是機(jī)體在各種致瘤因素作用下，局部組織的細(xì)胞在基因水平上失去對(duì)其生長(zhǎng)的正常調(diào)控，導(dǎo)致

23、克隆性異常增生而形成的新生物Mutation in tumour suppressor genes = brakes dont work, or there is an accumulations of mutations (DNA repair enzymes)是指能導(dǎo)致細(xì)胞惡性轉(zhuǎn)化的核酸片段。Second, when specific CD4+ T helper (TH) cells detect microbial (or self) antigen on non-cross-presenting tissue DCs, ligands for CC-chemokine receptor

24、 5 (CCR5) or CXC-chemokine receptor 3 (CXCR3) are produced that recruit CTLs into the infected tissue.抑癌基因在染色體中起穩(wěn)定性作用；正向調(diào)控信號(hào)：主要是起促進(jìn)細(xì)胞生長(zhǎng)和增殖，并且阻止其發(fā)生終末化傾向，癌基因起著這方面的作用。它的失活或突變具有促進(jìn)腫瘤生長(zhǎng)的潛勢(shì)。B：GAe組雛雞接種MDV GA株后40天，睪丸形成明顯腫瘤（如箭頭所示）；PROTO-ONCOGENES近來發(fā)現(xiàn)細(xì)胞中有抑制腫瘤發(fā)生的抑瘤基因。基因在細(xì)胞中拷貝數(shù)增加，從而使可用的轉(zhuǎn)錄模板數(shù)大大增加。惡性腫瘤細(xì)胞在生物學(xué)研究中的應(yīng)用

25、Benign tumors arise with great frequency but pose little risk because they are localized and small除了侵占正常細(xì)胞所占的空間外，還發(fā)生擴(kuò)散和轉(zhuǎn)移，形成新的病灶。In this figure, dashed arrows indicate antigen routing for crosspresentation.p53 functions as a molecular node in the DNA-damage responseA：GA0組睪丸正常（如箭頭所示）；p53 function惡性腫瘤

26、的分子生物學(xué)課件惡性腫瘤的分子生物學(xué)課件小 結(jié)正常細(xì)胞的生長(zhǎng)與增殖是由兩大類基因調(diào)控的正向調(diào)控信號(hào)：主要是起促進(jìn)細(xì)胞生長(zhǎng)和增殖，并且阻止其發(fā)生終末化傾向，癌基因起著這方面的作用。負(fù)向調(diào)控信號(hào)：主要使細(xì)胞成熟，促進(jìn)終末分化，最后是細(xì)胞調(diào)亡，抑癌基因則在這方面起作用。正常情況下這兩類信號(hào)保持著動(dòng)態(tài)平衡，十分精確地調(diào)控細(xì)胞增殖和成熟。一旦這兩類信號(hào)中有一類信號(hào)過強(qiáng)或過弱均會(huì)使細(xì)胞生長(zhǎng)失控而惡變。小 結(jié)正常細(xì)胞的生長(zhǎng)與增殖是由兩大類基因調(diào)控的惡性腫瘤細(xì)胞在生物學(xué)研究中的應(yīng)用 無限制增長(zhǎng)特性 細(xì)胞分化幼稚 細(xì)胞壽命長(zhǎng) 細(xì)胞的侵潤(rùn)性 致瘤性 細(xì)胞的遺傳性惡性腫瘤細(xì)胞在生物學(xué)研究中的應(yīng)用 無限制增長(zhǎng)特性蛋白

27、質(zhì)結(jié)構(gòu)未變化，但總量大大提高TUMOUR SUPRESSOR GENES負(fù)向調(diào)控信號(hào)：主要使細(xì)胞成熟，促進(jìn)終末分化，最后是細(xì)胞調(diào)亡，抑癌基因則在這方面起作用。c-MYC over-expressed in colon cancerRET - MEN 2aDCC - involved in colorectal cancerThe CCR4- and CCR5-mediated recruitment pathways are synergistic.借助交叉遞呈機(jī)制，APC可以主動(dòng)攝取病毒蛋白或腫瘤抗原，并通過MHC類分子將抗原呈遞給CD8+T細(xì)胞，從而產(chǎn)生有效的CTL應(yīng)答，達(dá)到清除靶細(xì)胞的目

28、的。The CCR4- and CCR5-mediated recruitment pathways are synergistic.Mutation in tumour suppressor genes = brakes dont work, or there is an accumulations of mutations (DNA repair enzymes)Helpless CTLs activated by unlicensed DCs die following secondary encounter with antigen in their effector phase近來發(fā)

29、現(xiàn)細(xì)胞中有抑制腫瘤發(fā)生的抑瘤基因。抑癌基因（tumorsuppressor gene，TSG）惡性腫瘤細(xì)胞在生物學(xué)研究中的應(yīng)用有時(shí)原癌基因中一個(gè)核苷酸的突變會(huì)使基因表達(dá)異常的蛋白產(chǎn)物，從而使細(xì)胞向惡性轉(zhuǎn)化。參與衰老過程，誘導(dǎo)細(xì)胞程序性死亡；蛋白質(zhì)結(jié)構(gòu)未變化，但總量大大提高它的失活或突變具有促進(jìn)腫瘤生長(zhǎng)的潛勢(shì)。1989年諾貝爾生理學(xué)或醫(yī)學(xué)獎(jiǎng)NormalTumourClonal selection of cancer cellsVariants over time蛋白質(zhì)結(jié)構(gòu)未變化，但總量大大提高NormalTumourCl經(jīng)典的抗原遞呈理論認(rèn)為：外源性抗原經(jīng)APC攝取后，在溶酶體中降解為短肽，由M

30、HC類分子提呈給CD4+T細(xì)胞；內(nèi)源性抗原在胞質(zhì)溶膠中降解后，與MHC類分子結(jié)合，提呈給CD8+T細(xì)胞，激活細(xì)胞毒性T淋巴細(xì)胞(CTL)殺傷病毒感染細(xì)胞或腫瘤細(xì)胞。然而，通常情況下病毒感染或發(fā)生異常突變的細(xì)胞主要為實(shí)質(zhì)細(xì)胞，它們大多不能遷移到淋巴器官與T細(xì)胞相互接觸，同時(shí)也缺乏T細(xì)胞活化所必須的共刺激信號(hào)，故不能活化初始型CD8+T細(xì)胞。經(jīng)典的抗原遞呈理論認(rèn)為：外/內(nèi)源性抗原示意圖外/內(nèi)源性抗原示意圖1976年，Bevan首先發(fā)現(xiàn)交叉遞呈(cross-presentation)的現(xiàn)象，隨后，Sigal等也揭示外源性抗原能有效被APC的MHC類分子遞呈。借助交叉遞呈機(jī)制，APC可以主動(dòng)攝取病毒蛋

31、白或腫瘤抗原，并通過MHC類分子將抗原呈遞給CD8+T細(xì)胞，從而產(chǎn)生有效的CTL應(yīng)答，達(dá)到清除靶細(xì)胞的目的。近年來更多研究表明，凋亡或壞死的細(xì)胞、熱休克蛋白、病毒蛋白、顆粒性抗原，甚至可溶性抗原等都可以通過交叉遞呈途徑活化CTL應(yīng)答。交叉遞呈在機(jī)體抗病毒及其它病原體感染和腫瘤免疫等方面起著非常重要的作用。1976年，Bevan首先發(fā)現(xiàn)交叉遞呈(cross-pres惡性腫瘤的分子生物學(xué)課件Activated proto-oncogene腫瘤細(xì)胞中常常不是由一種C-onc表達(dá)異常，有時(shí)需幾種C-onc發(fā)生改變，產(chǎn)生協(xié)同作用方可奏效借助交叉遞呈機(jī)制，APC可以主動(dòng)攝取病毒蛋白或腫瘤抗原，并通過MHC

32、類分子將抗原呈遞給CD8+T細(xì)胞，從而產(chǎn)生有效的CTL應(yīng)答，達(dá)到清除靶細(xì)胞的目的。B：GAe組雛雞接種MDV GA株后40天，睪丸形成明顯腫瘤（如箭頭所示）；1989年諾貝爾生理學(xué)或醫(yī)學(xué)獎(jiǎng)借助交叉遞呈機(jī)制，APC可以主動(dòng)攝取病毒蛋白或腫瘤抗原，并通過MHC類分子將抗原呈遞給CD8+T細(xì)胞，從而產(chǎn)生有效的CTL應(yīng)答，達(dá)到清除靶細(xì)胞的目的。RB1 - retinoblastoma susceptibility geneAct as a brake for cell divisionA：GA0組睪丸正常（如箭頭所示）；抑癌基因在染色體中起穩(wěn)定性作用；Licensed DCs upregulate e

33、xpression of co-stimulatory molecules, such as CD70, CD80 and CD86, and downregulate inhibitory molecules, such as programmed cell death ligand (PDL1).TLR具有激活DCs，增強(qiáng)其抗原交叉遞呈的能力。一旦這兩類信號(hào)中有一類信號(hào)過強(qiáng)或過弱均會(huì)使細(xì)胞生長(zhǎng)失控而惡變。正常情況下主要在胚胎期表達(dá)，在出生后的個(gè)體內(nèi)不表達(dá)或限量表達(dá)，主要功能是促進(jìn)細(xì)胞的正常增殖和分化，又稱原癌基因，被致癌因素激活時(shí)，可誘導(dǎo)細(xì)胞癌變。而不僅異?？焖僭鲋常壹?xì)胞可發(fā)生擴(kuò)散轉(zhuǎn)移

34、的稱為惡性腫瘤，特稱為癌（cancer）或新生物（neoplasm）。外源性抗原經(jīng)APC攝取后，在溶酶體中降解為短肽，由MHC類分子提呈給CD4+T細(xì)胞；交叉遞呈在機(jī)體抗病毒及其它病原體感染和腫瘤免疫等方面起著非常重要的作用。是指能導(dǎo)致細(xì)胞惡性轉(zhuǎn)化的核酸片段。Rous于1910年首先發(fā)現(xiàn)雞肉瘤病毒（后稱勞斯肉瘤病毒RSV）樹突狀細(xì)胞(DC)、巨噬細(xì)胞等專職APC都具有交叉活化CD8+T細(xì)胞的能力，而DC是體內(nèi)最有效的專職APC，抗原攝取能力強(qiáng)且能活化初始型T細(xì)胞，是執(zhí)行交叉遞呈功能的主要細(xì)胞。DC需要經(jīng)歷由不成熟向成熟階段的轉(zhuǎn)變才能有效刺激T細(xì)胞活化。不成熟DC捕獲抗原后，在炎性因子的刺激下分

35、化為成熟DC，細(xì)胞的抗原攝取能力下降，而抗原遞呈及刺激T細(xì)胞活化的能力增強(qiáng)。此過程同時(shí)伴隨細(xì)胞表面MHC類分子、類分子、共刺激分子CD80、CD86以及T細(xì)胞黏附分子CD48、CD58等的上調(diào)表達(dá)。此外，DC還通過延伸其樹突狀突起，增加與T細(xì)胞相互作用的機(jī)會(huì)。 Activated proto-oncogene樹突狀細(xì)胞(流式細(xì)胞術(shù)、激光共聚焦等新技術(shù)的應(yīng)用為研究抗原交叉遞呈的分子機(jī)制提供了保障；近年研究發(fā)現(xiàn)并非所有的DC亞型都能參與交叉遞呈，只有表達(dá)CD24, CD8和CD103 分子的DC才參與細(xì)胞交叉遞呈；TLR具有激活DCs，增強(qiáng)其抗原交叉遞呈的能力。流式細(xì)胞術(shù)、激光共聚焦等新技術(shù)的應(yīng)用

36、為研究抗原交叉遞呈的分子The molecular mechanisms involved in classical cross-priming are illustrated. Dendritic cells (DCs) take up antigen by distinct endocytosis mechanisms and present it to CD4+ T helper (TH) cells through MHC class II molecules and cross-present it to CD8+ cytotoxic T lymphocytes (CTLs) thr

37、ough MHC class I molecules. Activated CD4+ TH cells can stimulate CTLs through the production of interleukin-2 (IL-2) and license DCs for cross-priming through CD40 ligand (CD40L)CD40 interactions. Licensed DCs upregulate expression of co-stimulatory molecules, such as CD70, CD80 and CD86, and downr

38、egulate inhibitory molecules, such as programmed cell death ligand (PDL1). Toll-like receptor (TLR) ligands further activate DCs and increase their cross-presentation activity. Cross-primed CTLs are programmed for survival and cease TNF-related apoptosis-inducing ligand (TRAIL) production. Helpless

39、CTLs activated by unlicensed DCs die following secondary encounter with antigen in their effector phaseThe molecular mechanisms involChemokine-mediated regulation of cross-priming is illustrated. CD4+ TH cells, and the DCs they license, produce CC-chemokine ligand 3 (CCL3), CCL4 and CCL5 in the pres

40、ence of TLR ligands, which recruit naive CTLs for classical cross-priming. Alternatively, DCs licensed by natural killer T (NKT) cells produce the CC-chemokine receptor (CCR4) ligand CCL17, and NKT cells themselves produce the CCR4 ligand CCL22, which recruit naive CCR4+ CTLs for cross-priming. The

41、CCR4- and CCR5-mediated recruitment pathways are synergistic. In this figure, dashed arrows indicate antigen routing for crosspresentation. -GalCer, -galactosylceramide; TCR, T cell receptor.Chemokine-mediated regulation 借助交叉遞呈機(jī)制，APC可以主動(dòng)攝取病毒蛋白或腫瘤抗原，并通過MHC類分子將抗原呈遞給CD8+T細(xì)胞，從而產(chǎn)生有效的CTL應(yīng)答，達(dá)到清除靶細(xì)胞的目的。Loss

42、 of both copiesAct as a brake for cell division抑癌基因（tumorsuppressor gene，TSG）惡性腫瘤細(xì)胞在生物學(xué)研究中的應(yīng)用Caretaker genesAlternatively, DCs licensed by natural killer T (NKT) cells produce the CC-chemokine receptor (CCR4) ligand CCL17, and NKT cells themselves produce the CCR4 ligand CCL22, which recruit naive C

43、CR4+ CTLs for cross-priming.縱向傳播：原病毒隨細(xì)胞分裂傳遞外源性抗原經(jīng)APC攝取后，在溶酶體中降解為短肽，由MHC類分子提呈給CD4+T細(xì)胞；1976年，Bevan首先發(fā)現(xiàn)交叉遞呈(cross-presentation)的現(xiàn)象，隨后，Sigal等也揭示外源性抗原能有效被APC的MHC類分子遞呈。細(xì)胞癌基因（cellular oncogenes,C-onc）：存在于動(dòng)物細(xì)胞中的癌基因。The CCR4- and CCR5-mediated recruitment pathways are synergistic.惡性腫瘤細(xì)胞在生物學(xué)研究中的應(yīng)用In addition,

44、 recent studies have revealed two antigen-specific recruitment mechanisms: first, endothelial cells in certain tissues, such as the liver, pancreatic islets or the brain, can cross-present microbial antigen, which allows them to selectively recruit antigen-specific CTLs.DCC - involved in colorectal

45、cancer是指能導(dǎo)致細(xì)胞惡性轉(zhuǎn)化的核酸片段。Genetic Control of Neoplastic Initiation and PromotionTUMOUR SUPRESSOR GENESA：GA0組睪丸正常（如箭頭所示）；它的失活或突變具有促進(jìn)腫瘤生長(zhǎng)的潛勢(shì)。不成熟DC捕獲抗原后，在炎性因子的刺激下分化為成熟DC，細(xì)胞的抗原攝取能力下降，而抗原遞呈及刺激T細(xì)胞活化的能力增強(qiáng)。Tumour suppressor genes（腫瘤抑制基因）Loss of both copiesB：GA0組卵巢正常（如箭頭所示）；4 抑癌基因的作用及其致癌機(jī)制守門基因（gatekeeper gene）是

46、指在細(xì)胞惡性轉(zhuǎn)化過程中與癌基因啟動(dòng)相關(guān)的基因。此外，DC還通過延伸其樹突狀突起，增加與T細(xì)胞相互作用的機(jī)會(huì)。Mutation in tumour suppressor genes = brakes dont work, or there is an accumulations of mutations (DNA repair enzymes)Act as a brake for cell division交叉遞呈在機(jī)體抗病毒及其它病原體感染和腫瘤免疫等方面起著非常重要的作用。Rb (視網(wǎng)膜母細(xì)胞瘤)CDK4 - familial melanomaDendritic cells (DCs) ta

47、ke up antigen by distinct endocytosis mechanisms and present it to CD4+ T helper (TH) cells through MHC class II molecules and cross-present it to CD8+ cytotoxic T lymphocytes (CTLs) through MHC class I molecules.B：GAe組雛雞接種MDV GA株后40天，睪丸形成明顯腫瘤（如箭頭所示）；它的失活或突變具有促進(jìn)腫瘤生長(zhǎng)的潛勢(shì)。Act as a brake for cell divisi

48、onPROTO-ONCOGENES它的失活或突變具有促進(jìn)腫瘤生長(zhǎng)的潛勢(shì)。70年代中期，畢曉普和瓦慕斯發(fā)現(xiàn)動(dòng)物正常細(xì)胞中本來存在癌基因（原癌基因）；Loss of both copiesRAS - activated in many cancers (colon)A：GA0組睪丸正常（如箭頭所示）；Dendritic cells (DCs) take up antigen by distinct endocytosis mechanisms and present it to CD4+ T helper (TH) cells through MHC class II molecules and

49、cross-present it to CD8+ cytotoxic T lymphocytes (CTLs) through MHC class I molecules.70年代中期，畢曉普和瓦慕斯發(fā)現(xiàn)動(dòng)物正常細(xì)胞中本來存在癌基因（原癌基因）；有時(shí)原癌基因中一個(gè)核苷酸的突變會(huì)使基因表達(dá)異常的蛋白產(chǎn)物，從而使細(xì)胞向惡性轉(zhuǎn)化。它的失活或突變具有促進(jìn)腫瘤生長(zhǎng)的潛勢(shì)。Activated proto-oncogeneMET - hereditary papillary renal cancer4 抑癌基因的作用及其致癌機(jī)制Mutation in tumour suppressor genes = brakes dont work, or there is an accumulations of mutations (DNA repair enzymes)借助交叉遞呈機(jī)制，APC可以主動(dòng)攝取病毒蛋白或腫瘤抗原，并通過MH