腫瘤的生物學(xué)特性

1、u物質(zhì)代謝及酶的變化物質(zhì)代謝及酶的變化u腫瘤細(xì)胞的分化腫瘤細(xì)胞的分化u腫瘤細(xì)胞的生長(zhǎng)腫瘤細(xì)胞的生長(zhǎng)u腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制u腫瘤侵襲和轉(zhuǎn)移相關(guān)基因腫瘤侵襲和轉(zhuǎn)移相關(guān)基因核酸代謝核酸代謝核酸增多是腫瘤迅速生長(zhǎng)的物質(zhì)基礎(chǔ)核酸增多是腫瘤迅速生長(zhǎng)的物質(zhì)基礎(chǔ)DNADNA拓?fù)洚悩?gòu)酶拓?fù)洚悩?gòu)酶u物質(zhì)代謝及酶的變化物質(zhì)代謝及酶的變化端粒酶端粒酶DNADNA拓?fù)洚悩?gòu)酶拓?fù)洚悩?gòu)酶存在于細(xì)胞核內(nèi)的一類酶，他們能夠催化存在于細(xì)胞核內(nèi)的一類酶，他們能夠催化DNADNA鏈的鏈的斷裂和結(jié)合，從而控制斷裂和結(jié)合，從而控制DNADNA的拓?fù)錉顟B(tài)。的拓?fù)錉顟B(tài)。 DNADNA拓?fù)洚悩?gòu)酶通過(guò)形成短暫的單鏈裂解拓

2、撲異構(gòu)酶通過(guò)形成短暫的單鏈裂解- -結(jié)合循環(huán)，結(jié)合循環(huán)，催化催化DNADNA復(fù)制復(fù)制的拓?fù)洚悩?gòu)狀態(tài)的變化的拓?fù)洚悩?gòu)狀態(tài)的變化 核酸代謝核酸代謝u物質(zhì)代謝及酶的變化物質(zhì)代謝及酶的變化(A) Classification of human DNA topoisomerases. Type IB are the only enzymes that form cleavage complexes (cc) with 30-phosphotyrosyl (30-P-Y) intermediates.(C) Noncovalent binding of type IB enzymes. (D) Schem

3、e of the 30 phosphotyrosine covalent bond in the Top1cc. The arrow indicates the reversible (religation) reaction, which is favored under normal conditions. G) Scheme of the 50-phosphotyrosine covalent bond in the Top2cc. It is thought that length or integrity of chromosome end is used as a mitotic

4、counting mechanism in vitro 核酸代謝核酸代謝u物質(zhì)代謝及酶的變化物質(zhì)代謝及酶的變化端粒酶端粒酶Each mammalian chromosome end has a distinctive DNA-protein structure, which prevents the degradation and fusion of chromosome ends by helping distinguish chromosome ends from a double strand break in the genomic DNA.Mammalian have a stret

5、ch of a simple repeat sequence unit (TTAGGG) and in , length is 1520 kb. Fifty to 200 bp of the telomeric DNA shortens at each round of mitosis. When average DNA reaches a critically short length, about 47 kb, is arrested Irreversibly.核酸代謝核酸代謝端粒酶端粒酶u物質(zhì)代謝及酶的變化物質(zhì)代謝及酶的變化u物質(zhì)代謝及酶的變化物質(zhì)代謝及酶的變化核酸代謝核酸代謝蛋白質(zhì)代謝

6、蛋白質(zhì)代謝糖代謝糖代謝酶系統(tǒng)酶系統(tǒng)u物質(zhì)代謝及酶的變化物質(zhì)代謝及酶的變化酶系統(tǒng)酶系統(tǒng)增殖相關(guān)和分化相關(guān)的酶增殖相關(guān)和分化相關(guān)的酶轉(zhuǎn)化相關(guān)和演進(jìn)相關(guān)的酶轉(zhuǎn)化相關(guān)和演進(jìn)相關(guān)的酶細(xì)胞惡變的指標(biāo)。細(xì)胞惡變的指標(biāo)。主要正常細(xì)胞發(fā)生轉(zhuǎn)化，主要正常細(xì)胞發(fā)生轉(zhuǎn)化， 總可出現(xiàn)這類酶活性的總可出現(xiàn)這類酶活性的改變。改變。演進(jìn)相關(guān)的酶演進(jìn)相關(guān)的酶 酶活性于惡性程度呈平行關(guān)系的酶酶活性于惡性程度呈平行關(guān)系的酶轉(zhuǎn)化相關(guān)轉(zhuǎn)化相關(guān)u腫瘤細(xì)胞的分化腫瘤細(xì)胞的分化各種不同各種不同類型細(xì)胞類型細(xì)胞(分化細(xì)胞分化細(xì)胞)同一來(lái)源的同一來(lái)源的幼稚細(xì)胞幼稚細(xì)胞?分化的概念分化的概念特定的生理功能特定的生理功能特定的生化特征特定的生化特征

7、特定的形態(tài)結(jié)構(gòu)特定的形態(tài)結(jié)構(gòu)穩(wěn)定性穩(wěn)定性全能性全能性選擇性選擇性條件可逆性條件可逆性細(xì)胞分化特點(diǎn)細(xì)胞分化特點(diǎn):未分化惡性腫瘤是由于起源組織中的干細(xì)胞未分化惡性腫瘤是由于起源組織中的干細(xì)胞喪失了分化的能力。喪失了分化的能力。腫瘤細(xì)胞分化異常的機(jī)制腫瘤細(xì)胞分化異常的機(jī)制遺傳學(xué)改變遺傳學(xué)改變信號(hào)轉(zhuǎn)化異常信號(hào)轉(zhuǎn)化異常微環(huán)境的影響微環(huán)境的影響誘導(dǎo)分化治療腫瘤誘導(dǎo)分化治療腫瘤u腫瘤細(xì)胞的生長(zhǎng)腫瘤細(xì)胞的生長(zhǎng)細(xì)胞增殖活性的原位檢測(cè)方法及意義細(xì)胞增殖活性的原位檢測(cè)方法及意義細(xì)胞增殖活性：細(xì)胞增殖活性：細(xì)胞增生快慢的能力細(xì)胞增生快慢的能力DNA DNA 含量測(cè)定含量測(cè)定確定增生細(xì)胞的比例確定增生細(xì)胞的比例DNA

8、ploidy and proliferative activity as represented by the S-phase fraction (SPF).A link exists between high SPF values and increased risk of recurrence and death for patients with primary BC,Flow cytometry Flow cytometry 法法u腫瘤細(xì)胞的生長(zhǎng)腫瘤細(xì)胞的生長(zhǎng)免疫組織化學(xué)方法免疫組織化學(xué)方法Several monoclonal antibodies reacting with diff

9、erent proliferating cell nuclear antigens have been described, such as PCNA, Ki-67 and MIB 1, KiS1 and others.The Ki-67/MIB 1 protein has a prognostic value for many types of malignant tumors.Ki-67Only papers published in English in peer reviewed journals before June 2004 that include at least 100 e

10、valuable patients were selected. Inaddition, the prognostic and predictive role of the proliferative markers had to be assessed through multivariate analyses. One hundred and thirty-two papers fulfilled these criteria and 159 516 patients analyzed.u腫瘤細(xì)胞的生長(zhǎng)腫瘤細(xì)胞的生長(zhǎng)免疫組織化學(xué)方法免疫組織化學(xué)方法細(xì)胞周期蛋白細(xì)胞周期蛋白The diffe

11、rent cyclins：the concentration rise and fall at specific stages throughout the cell cycle, have a temporally distinct and highly regulated pattern of expression, i.e. they are synthesized and degraded at specific stages of the cell cycle.Cyclin E is the limiting factor for G1 phase progression and S

12、 phase entryRecently, several splice variants of cyclin E1, which are not present in normal cells, have also been discovered; which stimulate cells to progress through the cell cycle much more efficiently than the full length cyclin E1Cyclin E was prognostic in seven out of 10 studies.u腫瘤細(xì)胞的生長(zhǎng)腫瘤細(xì)胞的生

13、長(zhǎng)免疫組織化學(xué)方法免疫組織化學(xué)方法細(xì)胞周期蛋白細(xì)胞周期蛋白The overexpression of cyclin E was accompanied by the appearance of low molecular weight (LMW) isoforms, and both were a reliable prognostic marker in stage IIII BC patients.High levels of cyclin E1 were predictive of resistance to tamoxifen adjuvant therapy in 108 node-

14、positive BC patients, independently of ER status.Cyclin D1u腫瘤細(xì)胞的生長(zhǎng)腫瘤細(xì)胞的生長(zhǎng)細(xì)胞周期蛋白細(xì)胞周期蛋白D-type cyclins are other key regulator proteins of the G1 phase progression.The protein is synthesized in response togrowth factors; its levels reach a maximum in the mid-G1phase of the cell cycle and then begin to

15、drop. It appears that the association of cyclin D1 to Cdk is crucial to drive cells to the restriction point where the cell is committed to divideA strong correlation between overexpression of cyclin D1 and HR-positivity has been reported in the majority of trials, but cyclin D1 does not appear to b

16、e a strong prognosticmarker. In fact, its overexpression has been associated with better RFS in only one studyCyclin D1u腫瘤細(xì)胞的生長(zhǎng)腫瘤細(xì)胞的生長(zhǎng)細(xì)胞周期蛋白細(xì)胞周期蛋白u(yù)腫瘤的生長(zhǎng)與擴(kuò)散腫瘤的生長(zhǎng)與擴(kuò)散l腫瘤的擴(kuò)散方式腫瘤的擴(kuò)散方式直接蔓延直接蔓延轉(zhuǎn)移轉(zhuǎn)移metastasismetastasis瘤細(xì)胞從原發(fā)部位瘤細(xì)胞從原發(fā)部位 侵入淋巴管、血管和體腔，侵入淋巴管、血管和體腔，擴(kuò)散到其它部位，擴(kuò)散到其它部位， 形成與原發(fā)瘤形成與原發(fā)瘤相同的腫瘤。相同的腫瘤。轉(zhuǎn)移轉(zhuǎn)移meta

17、stasismetastasisu腫瘤的生長(zhǎng)與擴(kuò)散腫瘤的生長(zhǎng)與擴(kuò)散腫瘤的擴(kuò)散方式腫瘤的擴(kuò)散方式淋巴道轉(zhuǎn)移淋巴道轉(zhuǎn)移Lymphatic metastasis is a predictor of poor Lymphatic metastasis is a predictor of poor outcome in many solid malignancies .outcome in many solid malignancies . The presence of lymph node metastases The presence of lymph node metastases decrea

18、ses the 5-year survival of melanoma decreases the 5-year survival of melanoma patients independent of other prognostic patients independent of other prognostic factors of the primary tumor.factors of the primary tumor.Figure 1. Development of lymphatic vessels in embryogenesis and cancerSome of the

19、proteins that are important in theseevents are shown underneath each section.Arrows denote the direction of lymph flow in thelymphatic vessels.轉(zhuǎn)移轉(zhuǎn)移metastasismetastasisu腫瘤的生長(zhǎng)與擴(kuò)散腫瘤的生長(zhǎng)與擴(kuò)散腫瘤的擴(kuò)散方式腫瘤的擴(kuò)散方式血道轉(zhuǎn)移血道轉(zhuǎn)移轉(zhuǎn)移轉(zhuǎn)移metastasismetastasisu腫瘤的生長(zhǎng)與擴(kuò)散腫瘤的生長(zhǎng)與擴(kuò)散l腫瘤的擴(kuò)散方式腫瘤的擴(kuò)散方式種植性轉(zhuǎn)移種植性轉(zhuǎn)移體腔內(nèi)臟器的腫瘤蔓延至器官表面時(shí)，體腔內(nèi)臟器的腫瘤蔓延至

20、器官表面時(shí)， 瘤細(xì)胞可脫落種植于瘤細(xì)胞可脫落種植于體腔和各器官表面形成多數(shù)轉(zhuǎn)移瘤。體腔和各器官表面形成多數(shù)轉(zhuǎn)移瘤。u腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤侵襲是轉(zhuǎn)移的前提；腫瘤侵襲是轉(zhuǎn)移的前提；侵襲和轉(zhuǎn)移的步驟：侵襲和轉(zhuǎn)移的步驟：脫離原發(fā)瘤群體脫離原發(fā)瘤群體向周?chē)M織浸潤(rùn)向周?chē)M織浸潤(rùn)與局部血管或淋巴管密切接觸，與局部血管或淋巴管密切接觸， 穿過(guò)穿過(guò)其管壁其管壁穿透管壁，穿透管壁， 在基質(zhì)中增生在基質(zhì)中增生轉(zhuǎn)移灶的形成和生長(zhǎng)轉(zhuǎn)移灶的形成和生長(zhǎng)u腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制l細(xì)胞黏附與細(xì)胞黏附分子細(xì)胞黏附與細(xì)胞黏附分子侵襲和轉(zhuǎn)移的步驟：侵襲和轉(zhuǎn)移的步驟：脫離原發(fā)瘤群體脫

21、離原發(fā)瘤群體以配體核受體結(jié)合的形式，以配體核受體結(jié)合的形式， 使細(xì)胞間發(fā)生粘連使細(xì)胞間發(fā)生粘連integrin跨膜糖蛋白跨膜糖蛋白十六種十六種a a亞單位和亞單位和8 8種種b b亞單位亞單位u腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制l細(xì)胞黏附與細(xì)胞黏附分子細(xì)胞黏附與細(xì)胞黏附分子cadherin與細(xì)胞骨架連接與細(xì)胞骨架連接人類至少有人類至少有1010多種鈣粘蛋白多種鈣粘蛋白E E； N N； P Pu腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制l細(xì)胞黏附與細(xì)胞黏附分子細(xì)胞黏附與細(xì)胞黏附分子IgSF跨膜蛋白跨膜蛋白具有與具有與IgIg類似的結(jié)構(gòu)類似的結(jié)構(gòu)u腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞擴(kuò)散的

22、過(guò)程機(jī)制l細(xì)胞黏附與細(xì)胞黏附分子細(xì)胞黏附與細(xì)胞黏附分子Selectin familycancer cells adhere to by a process similar to that of LC homing. In this model, cells in flow are captured on the endothelial surface.transient adhesive interactions by cells with endothelial selectins(rolling), and firmly anchored on (firm adhesion) to ena

23、ble entry into the underlying tissue. The selectins, particularly E-selectin, are recognized to mediate adhesion and thus potentiate of certain cancersu腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制l細(xì)胞黏附與細(xì)胞黏附分子細(xì)胞黏附與細(xì)胞黏附分子Selectin familyu腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制l細(xì)胞黏附與細(xì)胞黏附分子細(xì)胞黏附與細(xì)胞黏附分子CD44A transmembrane protein Essential for

24、the homing and properties of leukemicCells, CD44 has also been found to support anchorage-independent growth in vitro and tumor growth and in experimental models of solid cancers u腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞擴(kuò)散的過(guò)程機(jī)制腫瘤細(xì)胞從原發(fā)灶分離的機(jī)制腫瘤細(xì)胞從原發(fā)灶分離的機(jī)制腫瘤細(xì)胞表面黏附分子減少。腫瘤細(xì)胞表面黏附分子減少。癌細(xì)胞鈣含量降低癌細(xì)胞鈣含量降低惡性腫瘤細(xì)胞間連接結(jié)構(gòu)數(shù)量減少惡性腫瘤細(xì)胞間連接結(jié)構(gòu)數(shù)量減少

25、腫瘤細(xì)胞表面電荷增加腫瘤細(xì)胞表面電荷增加l腫瘤細(xì)胞向周?chē)M織的浸潤(rùn)腫瘤細(xì)胞向周?chē)M織的浸潤(rùn)細(xì)胞外基質(zhì)的降解細(xì)胞外基質(zhì)的降解瘤細(xì)胞的運(yùn)動(dòng)瘤細(xì)胞的運(yùn)動(dòng)趨化因子的作用趨化因子的作用腫瘤血管生成腫瘤血管生成腫瘤血管生成腫瘤血管生成l腫瘤細(xì)胞向周?chē)M織的浸潤(rùn)腫瘤細(xì)胞向周?chē)M織的浸潤(rùn)腫瘤血管生成腫瘤血管生成腫瘤組織中微血管的來(lái)源腫瘤組織中微血管的來(lái)源瘤細(xì)胞生成的多種生長(zhǎng)因子瘤細(xì)胞生成的多種生長(zhǎng)因子誘導(dǎo)瘤體生成微血管誘導(dǎo)瘤體生成微血管殘存于流體的宿主血管逐漸殘存于流體的宿主血管逐漸變?yōu)槟[瘤血管變?yōu)槟[瘤血管VEGFVEGF是迄今鑒定出來(lái)的是迄今鑒定出來(lái)的最重要的血管生成因子最重要的血管生成因子Fig. 1 S

26、witching on the angiogenic phenotype in tumors by genetic and epigenetic factors. Both malignant and nonmalignant cells produce multiple angiogenic factors and cytokines to induce tumor neovascularization. Endogenous angiogenesis inhibitors are down regulated to support the angiogenic phenotype腫瘤細(xì)胞侵

27、入血管和淋巴管腫瘤細(xì)胞侵入血管和淋巴管侵入血管和淋巴管侵入血管和淋巴管在循環(huán)中運(yùn)行到達(dá)遠(yuǎn)處部位在循環(huán)中運(yùn)行到達(dá)遠(yuǎn)處部位Fig. 1. Schematic diagram showing how production of VEGF-C and VEGF-C in tumors can induce lymphangiogenesis, leading to increased lymphatic vessel density in the vicinity of the tumor, and subsequently to metastasis of invasive tumor cells

28、via the lymph vessels. Fig. 1. l轉(zhuǎn)移灶的形成和生長(zhǎng)轉(zhuǎn)移灶的形成和生長(zhǎng)u腫瘤侵襲和轉(zhuǎn)移相關(guān)基因腫瘤侵襲和轉(zhuǎn)移相關(guān)基因Nm23Nm23基因基因NM23-H1 and NM23-H2 in humanNucleoside diphosphate kinases (NDPKs) catalyze the exchange of -phosphate between nucleoside (and 2-deoxynucleoside) triphosphates and diphosphates with formation of a high-energy phosph

29、ohistidine intermediate(Parks and Agarwal 1973). They are encoded by the NME genes (also known as NM23).參與調(diào)節(jié)細(xì)胞內(nèi)微管系統(tǒng)的狀態(tài)參與調(diào)節(jié)細(xì)胞內(nèi)微管系統(tǒng)的狀態(tài)高度表達(dá)高度表達(dá)nm23nm23表現(xiàn)為低轉(zhuǎn)移屬性表現(xiàn)為低轉(zhuǎn)移屬性u(píng)腫瘤侵襲和轉(zhuǎn)移相關(guān)基因腫瘤侵襲和轉(zhuǎn)移相關(guān)基因腫瘤轉(zhuǎn)移相關(guān)基因腫瘤轉(zhuǎn)移相關(guān)基因mtalu腫瘤侵襲和轉(zhuǎn)移相關(guān)基因腫瘤侵襲和轉(zhuǎn)移相關(guān)基因Tiam1 基因基因鼠鼠T淋巴細(xì)胞瘤中克隆出來(lái)的基因。淋巴細(xì)胞瘤中克隆出來(lái)的基因。產(chǎn)物具有產(chǎn)物具有1591個(gè)氨基酸殘基，個(gè)氨基酸殘基， 把蛋

30、白質(zhì)錨定在質(zhì)膜上把蛋白質(zhì)錨定在質(zhì)膜上TIAM1 T-cell lymphoma invasion and metastasis 1 Homo sapiens Zhonghua Bing Li Xue Za Zhi. 2009 Apr;38(4):268-72.Overexpression of Tiam1 gene and its relationship with invasive and metastatic ability of nasopharyngeal carcinoma.Article in ChineseZhang XM, Ding Y, Chen JZ, Jin H, Yu

31、LN, Li YF, Ding YQ.Currently, many GEFs, including Vav1, LARG, Bcr and T-lymphoma invasion and metastasis 1 (Tiam1), have been identified as oncogenes.RESULTS: Tiam1 over expression significantly increased the abilities of adhesion, migratory and invasion of C666-1 and CNE1 cells, comparing with tha

32、t of the control untransfected cells (P 0.05).CONCLUSION: Tiam1 expression correlates with the invasion and metastasis of nasopharyngeal carcinoma cells.u腫瘤侵襲和轉(zhuǎn)移相關(guān)基因腫瘤侵襲和轉(zhuǎn)移相關(guān)基因Tiam1 基因基因鼠鼠T淋巴細(xì)胞瘤中克隆出來(lái)的基因。淋巴細(xì)胞瘤中克隆出來(lái)的基因。Overexpression of Tiam1 in hepatocellular carcinomas predicts poor prognosis of HCC

33、 patientsYi Ding1, Bin Chen2, Shuang Wang3, Liang Zhao3, Juanzhi Chen3, Yanqing Ding3, Longhua Chen1* and Rongcheng Luo2*Int. J. Cancer: 124, 653658 (2009)2008 Wiley-Liss, Inc.u腫瘤侵襲和轉(zhuǎn)移相關(guān)基因腫瘤侵襲和轉(zhuǎn)移相關(guān)基因Tiam1 基因基因 鼠鼠T淋巴細(xì)胞瘤中克隆出來(lái)的基因。淋巴細(xì)胞瘤中克隆出來(lái)的基因。生長(zhǎng)因子通過(guò)生長(zhǎng)因子通過(guò)Ras信號(hào)通路，信號(hào)通路， 導(dǎo)致細(xì)胞增殖。導(dǎo)致細(xì)胞增殖。轉(zhuǎn)染給轉(zhuǎn)染給NIH3T3細(xì)胞，細(xì)胞，

34、引起大量侵襲和轉(zhuǎn)移。引起大量侵襲和轉(zhuǎn)移。Activated KrasG12D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherinBritish Journal of Cancer 104, 1038-1048 (15 March 2011) S Rachagani, S Senapati, S Chakraborty, M P Ponnusamy, S Kumar, L M Smith, M Jain and S K Batra u腫瘤侵襲和轉(zhuǎn)移相關(guān)