癌癥干細(xì)胞假說

傳統(tǒng)觀點認(rèn)為，癌癥是環(huán)境或內(nèi)部因素誘導(dǎo)正常細(xì)胞內(nèi)的關(guān)鍵致癌基因和腫瘤抑制基因突變導(dǎo)致的一種疾病。當(dāng)這些突變導(dǎo)致細(xì)胞向更原始、高度增殖狀態(tài)轉(zhuǎn)化，克隆擴張形成白血病或?qū)嶓w腫瘤時，就會出現(xiàn)癌癥的臨床表現(xiàn)¹。然而，這種模式不能夠*解釋許多腫瘤和轉(zhuǎn)移瘤的長發(fā)育延遲，產(chǎn)生細(xì)胞去分化和細(xì)胞永生的起始誘導(dǎo)機制，或腫瘤本身內(nèi)的細(xì)胞功能和表型多樣性起源。過去十年中，越來越多的證據(jù)表明，惡性腫瘤起源于組織干細(xì)胞在突變作用下的轉(zhuǎn)化，這些突變會導(dǎo)致控制干細(xì)胞生長和增殖的正常機制的調(diào)節(jié)異常^1-9。

成體干細(xì)胞填充每個器官內(nèi)的離散區(qū)位。它們具有長生命期和多能性能，可以重新轉(zhuǎn)化成該器官內(nèi)的所有類型的細(xì)胞。干細(xì)胞的兩個顯著特性是：

1. 在長期的區(qū)位環(huán)境中保持休眠的能力，

2. 不對稱細(xì)胞分裂能力，可分裂為一個干細(xì)胞（稱作自我更新）和一個分化的子代。

支持CSC假說的例證

此外，干細(xì)胞具有細(xì)胞凋亡耐受性，具有增強的端粒酶和DNA修復(fù)活性，并且具有膜結(jié)合的ABC轉(zhuǎn)運蛋白，能夠排除異物，從而使干細(xì)胞相對耐受劑和其他外源性毒物的損傷作用^9-11 。自我更新加上長休眠期，使接觸損傷劑的干細(xì)胞能積聚可能隨著時間推移導(dǎo)致惡性轉(zhuǎn)化的突變³。

癌癥干細(xì)胞鑒定

研究人員已經(jīng)從大多數(shù)白血病^2,4,13以及許多實體瘤（如腦膠質(zhì)母細(xì)胞瘤和成神經(jīng)管細(xì)胞瘤^4,5,10,14,15 、乳腺^3,16 、子宮頸、結(jié)腸直腸^17,18 、胃腸道、肝細(xì)胞、肺、胰腺、前列腺和皮膚癌^6,9,19,20）中分離得到少量的干細(xì)胞樣細(xì)胞。癌癥干細(xì)胞與其對應(yīng)的正常干細(xì)胞具有相同的細(xì)胞表面標(biāo)記物（見表1），但卻表現(xiàn)出不受控制的增殖，這可能是由于對負(fù)生長調(diào)節(jié)因子或?qū)佑|抑制和間隙連接細(xì)胞間通訊（GJIC）缺失的響應(yīng)性降低所致。^1,10

產(chǎn)品特點

AldeRed ALDH檢測分析

癌癥干細(xì)胞醛脫氫酶（ALDH）的表達(dá)量升高，被認(rèn)為是所有CSCs的標(biāo)志。ALDEFLUOR™檢測試劑盒過去一直用于測量ALDH的表達(dá)水平，并廣泛用于研究罕見的CSC群體。ALDEFLUOR檢測試劑盒的發(fā)射波長位于電磁光譜的綠色區(qū)域（512nm）。因此，其中的試劑不能同時用于表達(dá)綠色熒光蛋白（發(fā)射綠色熒光光譜）的細(xì)胞或小鼠。AldeRed是用于標(biāo)記活A(yù)LDH陽性細(xì)胞的ALDH紅移熒光底物，從而釋放出綠色發(fā)射通道以幫助同步完成其他檢測。AldeRed克服了ALDEFLUOR檢測試劑盒目前的局限。

閱讀《Nature》中關(guān)于AldeRed的文章

AldeRed的特性和優(yōu)點：

• 紅移檢測釋放出其他實驗所需的綠色通道

• 活體干細(xì)胞鑒定技術(shù)，能夠?qū)币姷募?xì)胞群體進行流式分選

• 快速酶反應(yīng)檢測方案

AldeRed 588-A是一種無毒的ALDH熒光底物，能夠自由進入完整活細(xì)胞但其被ALDH轉(zhuǎn)化成酸產(chǎn)物后仍將滯留在細(xì)胞內(nèi)。

癌癥干細(xì)胞信號轉(zhuǎn)導(dǎo)通路

干細(xì)胞巢被充滿時，正常干細(xì)胞的自我更新將終止。與正常干細(xì)胞不同，癌癥干細(xì)胞和干細(xì)胞源癌祖細(xì)胞的不受控自我更新會超過其區(qū)位并滲入周圍組織¹³。Hedgehog，Notch，Wnt，和PTEN是控制正常和癌癥干細(xì)胞自我更新、增殖和存活的部分途徑。在大多數(shù)侵襲性癌癥中，都可觀察到導(dǎo)致這些途徑不同程度激活的突變。

Hedgehog 和 Bmi1通路

Hedgehog（Hh）通路能夠調(diào)節(jié)成體干細(xì)胞的休眠和自我更新。研究人員已經(jīng)在哺乳動物中鑒定了三種Hh配體，即Sonic hedgehog（Shh）、Desert hedgehog（Dhh）和Indian hedgehog（Ihh），其中對Shh的研究多。在沒有配體的情況下，Hh受體PTCH1通過催化抑制跨膜蛋白Smoothened（SMO），從而抑制信號轉(zhuǎn)導(dǎo)。配體與PTCH1可使受體失活，并活化SMO，繼而誘導(dǎo)Gli轉(zhuǎn)錄因子；Gli1和Gli2是Hh信號通路的陽性信號介導(dǎo)子，而Gli3是負(fù)調(diào)節(jié)子^3,20。

Bmi1的誘導(dǎo)能夠促進許多Hh活化的效應(yīng)。Bmi1 是一個的多梳基因，通過染色質(zhì)重塑抑制轉(zhuǎn)錄，并能夠下調(diào)Ink-4A / ADP核糖基化因子（ARF）復(fù)合物（如p16 Ink4A 和p19 ARF）的基因表達(dá)——這些基因是細(xì)胞周期的負(fù)調(diào)節(jié)物并且參與干細(xì)胞的休眠和分化^3,4。這使得Hh通路元件PTCH1、Gli1和Gli2表達(dá)上調(diào)^19,20， 以及Gli1和Gli2誘導(dǎo)的生長促進基因cyclin D1、Myc和Snail表達(dá)來實現(xiàn)干細(xì)胞分化和自我更新。

Notch-γ-分泌酶通路

Notch信號轉(zhuǎn)導(dǎo)能夠促進正常神經(jīng)干細(xì)胞的存活和增殖，抑制它們的分化。許多癌細(xì)胞系（包括T細(xì)胞白血病，以及腦、乳腺、卵巢、宮頸、結(jié)腸直腸、胰腺、唾液腺和肺部癌癥^3,6,9,15 ）的干細(xì)胞樣細(xì)胞中，Notch信號轉(zhuǎn)導(dǎo)通路被高度激活。其中，成神經(jīng)管細(xì)胞瘤和T細(xì)胞淋巴細(xì)胞白血病是Notch依賴性的惡性腫瘤¹⁵。

Notch通路激活包括通過γ-分泌酶對Notch配體/受體復(fù)合物進行蛋白水解切割，從而釋放Notch胞內(nèi)結(jié)構(gòu)域片段（NICD），移位到細(xì)胞核并上調(diào)Myc、Hes1和其他基因的表達(dá)。當(dāng)用NICD2轉(zhuǎn)染DAOY成神經(jīng)管細(xì)胞瘤細(xì)胞系使Notch通路持續(xù)激活時，轉(zhuǎn)染后的細(xì)胞比非轉(zhuǎn)染的DAOY細(xì)胞產(chǎn)生更多的異種移植腫瘤，培養(yǎng)物中CD133 +和側(cè)群干細(xì)胞樣細(xì)胞也增加了。相反，抑制γ-分泌酶可將側(cè)群細(xì)胞減少至總細(xì)胞計數(shù)的0.01％，并且抑制90％的細(xì)胞形成軟瓊脂集落及在免疫受損的小鼠中形成腫瘤異種移植物的能力。NICD2轉(zhuǎn)染可保護細(xì)胞免受γ-分泌酶抑制的影響¹⁵。因此，在一些腫瘤類型中，抑制Notch信號轉(zhuǎn)導(dǎo)可以消除腫瘤起始所需的細(xì)胞群。

Wnt-β-連環(huán)蛋白途徑

Wnt包含結(jié)合Frizzled（Fz）受體家族的19種胞外糖蛋白家族，其可激活抑制β-連環(huán)蛋白的蛋白水解降解途徑，這使得β-連環(huán)蛋白在細(xì)胞質(zhì)中積累并向細(xì)胞核轉(zhuǎn)運。在細(xì)胞核中，β-連環(huán)蛋白通過Tcf / Lef轉(zhuǎn)錄因子促進基因轉(zhuǎn)錄。在Wnt未激活的情況下，軸蛋白（Axin）和腺瘤 息肉病大腸桿菌蛋白（APC）與糖原合酶激酶3（Gsk3）形成復(fù)合物，從而促進細(xì)胞質(zhì)β-連環(huán)蛋白磷酸化，繼而靶向β-連環(huán)蛋白以進行蛋白水解降解。

Wnt通路的激活需要Fz與其共同受體（LDL受體樣蛋白5/6（Lrp5 / 6））的結(jié)合。Wnt / Fz / Lrp5 / 6復(fù)合物的形成激活磷蛋白Dishevelled（Dvl）（Fz受體的組成成分），繼而招募Axin / Gsk3，從而解離Axin / APC / Gsk3復(fù)合物。Lrp5 / 6被Gsk3和酪蛋白激酶1γ（Ck1γ）。 磷酸化的Lrp5 / 6結(jié)合Axin / Gsk3形成復(fù)合體，防止β-連環(huán)蛋白的磷酸化從而穩(wěn)定β-連環(huán)蛋白。

圖1. 癌癥干細(xì)胞中關(guān)鍵發(fā)育信號轉(zhuǎn)導(dǎo)通路的激活。Shh、Wnt和Notch信號轉(zhuǎn)導(dǎo)途徑與維持癌癥干細(xì)胞的致瘤潛力有關(guān)。通過與Bmi1信號轉(zhuǎn)導(dǎo)介體和其他自我更新基因（如Nanog和Sox-2）的相互作用，這些新的調(diào)節(jié)機制可以促進或抑制自我更新，從而提供癌癥治療干預(yù)的方法。

材料

Product # Image Description Molecular Formula Add to Cart A3230 AR-A014418 ≥98% (HPLC), solid C12H12N4O4S 價格 B1686 BIO ≥98% (HPLC) C16H10BrN3O2 價格 B9678 Monoclonal Anti-Bone Morphogenetic Protein 4 antibody produced in mouse clone 66119.11, purified immunoglobulin, lyophilized powder 價格 B7185 Anti-Breast Cancer Resistance Protein antibody produced in rabbit affinity isolated antibody, buffered aqueous solution 價格 B7684 Monoclonal Anti-Breast Cancer Resistance Protein antibody produced in mouse 250 μg/mL, clone BXP-34, tissue culture supernatant, aqueous solution 價格 B7059 Monoclonal Anti-Breast Cancer Resistance Protein antibody produced in mouse ~250 μg/mL, clone BXP-21, tissue culture supernatant, aqueous solution 價格 C2206 Anti-β-Catenin antibody produced in rabbit whole antiserum 價格 C7082 Monoclonal Anti-β-Catenin antibody produced in mouse clone 6F9, ascites fluid 價格 C7207 Monoclonal Anti-β-Catenin antibody produced in mouse clone 15B8, ascites fluid 價格 P7437 Monoclonal Anti-CD19?PE antibody produced in mouse clone SJ25-C1, purified immunoglobulin, buffered aqueous solution 價格 HPA005785 Anti-CD44 antibody produced in rabbit Prestige Antibodies®Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution 價格 C7923 Monoclonal Anti-CD44 antibody produced in mouse clone A3D8, purified immunoglobulin, buffered aqueous solution 價格 HPA000440 Anti-CD45 antibody produced in rabbit Prestige Antibodies®Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution 價格 C9819 Chondroitin sulfate A sodium salt from bovine trachea lyophilized powder, BioReagent, suitable for cell culture 價格 C3116 Anti-CXCR4 antibody produced in rabbit affinity isolated antibody, buffered aqueous solution 價格 C6598 Monoclonal Anti-CXCR4 (Fusin) antibody produced in mouse clone 44716, purified immunoglobulin, lyophilized powder 價格 C8352 Anti-CXCR4 (Fusin) (182-196) antibody produced in rabbit IgG fraction of antiserum, buffered aqueous solution 價格 C8227 Anti-CXCR4 (Fusin), N-Terminal antibody produced in rabbit IgG fraction of antiserum, buffered aqueous solution 價格 D5942 DAPT ≥98% (HPLC), solid C23H26F2N2O4 價格 D0817 (?)-Deguelin >98% (HPLC), powder C23H22O6 價格 E1270 ECM Gel from Engelbreth-Holm-Swarm murine sarcoma liquid, BioReagent, suitable for cell culture 價格 F3542 Fibronectin Fragment III1-C human recombinant, expressed in E. coli, lyophilized powder, ≥90% (SDS-PAGE) 價格 F3804 Anti-Frizzled-1 antibody produced in rabbit affinity isolated antibody, buffered aqueous solution 價格 F3179 Anti-Frizzled-3 antibody produced in rabbit affinity isolated antibody, buffered aqueous solution 價格 F3429 Anti-Frizzled-4 antibody produced in rabbit affinity isolated antibody, buffered aqueous solution 價格 F3679 Anti-Frizzled-7 antibody produced in rabbit affinity isolated antibody, buffered aqueous solution 價格 P7965 Monoclonal Anti-P-Glycoprotein (MDR) antibody produced in mouse clone F4, ascites fluid 價格 HPA003539 Anti-IL3RA antibody produced in rabbit Prestige Antibodies®Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution 價格 J4127 Anti-Jagged 1 antibody produced in goat affinity isolated antibody, lyophilized powder 價格 J4145 Jervine ≥98% (HPLC), powder C27H39NO3 價格 L1790 L-685,458 >96% (HPLC), solid C39H52O6N4 價格 L4020 Monoclonal Anti-LEF-1 (β-Catenin binding domain) antibody produced in mouse clone REMB1, ~1 mg/mL, purified immunoglobulin, buffered aqueous solution 價格 T2949 Anti-mTOR antibody produced in rabbit 1.0-1.5 mg/mL, affinity isolated antibody, buffered aqueous solution 價格 N8523 Monoclonal Anti-NF-κB antibody produced in mouse clone NF-12, ascites fluid 價格 N6786 Monoclonal Anti-Notch1 antibody produced in mouse clone mN1A, purified immunoglobulin, buffered aqueous solution 價格 N9286 Notch-1/Fc Chimera from rat recombinant, expressed in NSO cells, ≥90% (SDS-PAGE), lyophilized powder, from rat 價格 N9161 Notch-2/Fc Chimera from rat recombinant, expressed in NSO cells, ≥90% (SDS-PAGE), lyophilized powder 價格 P4235 Anti-p53 antibody produced in sheep fractionated antiserum, buffered aqueous solution 價格 P5813 Monoclonal Anti-p53 antibody produced in mouse clone BP53-12, ascites fluid 價格 P8999 Monoclonal Anti-p53 antibody produced in mouse clone DO-7, purified from hybridoma cell culture 價格 P7874 Monoclonal Anti-p53 antibody produced in mouse ~2 mg/mL, clone DO-2, purified immunoglobulin, buffered aqueous solution 價格 P6874 Monoclonal Anti-p53 antibody produced in mouse clone DO-1, purified from hybridoma cell culture 價格 P0667 Parthenolide ≥98% (HPLC) C15H20O3 價格 P4707 Poly-L-lysine solution mol wt 70,000-150,000, 0.01%, sterile-filtered, BioReagent, suitable for cell culture 價格 P4832 Poly-L-lysine solution mol wt 150,000-300,000, 0.01%, sterile-filtered, BioReagent, suitable for cell culture 價格 P7482 Anti-PTEN antibody produced in rabbit IgG fraction of antiserum, buffered aqueous solution 價格 P3487 Monoclonal Anti-PTEN antibody produced in mouse ~1 mg/mL, purified immunoglobulin, clone PTN-18, buffered aqueous solution 價格 R1276 Reversin 121 ≥97% (HPLC), powder C34H47N3O9 價格 R1401 Reversin 205 ≥98% (HPLC), film C41H58N4O12 價格 S4572 SANT-1 ≥98% (HPLC), powder C23H27N5 價格 S2188 γ-Secretase inhibitor ≥90% (TLC), powder C33H57F2N5O9 價格 S9819 Anti-Smoothened Drosophila Homolog antibody produced in rabbit affinity isolated antibody 價格 S0191 Sonic Hedgehog Peptide from mouse ≥97% (SDS-PAGE), recombinant, expressed in E. coli, Fused to a histidine tag at the C-terminus, lyophilized powder 價格 S8321 Monoclonal Anti-Sonic Hedgehog (Shh) 小鼠抗 clone SH154, purified from hybridoma cell culture 價格 S4944 Monoclonal Anti-Sonic Hedgehog (N-terminal) antibody produced in rat clone 171018, purified immunoglobulin, lyophilized powder 價格 S5174 SPARC from murine parietal yolk sac (PYS-2) cells ~80% (SDS-PAGE), lyophilized powder 價格 HPA001671 Anti-STAT3 antibody produced in rabbit Prestige Antibodies®Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution 價格 S5933 Anti-STAT3 antibody produced in rabbit IgG fraction of antiserum, buffered aqueous solution 價格 V1014 Anti-Vascular Endothelial Growth Factor Receptor 2 antibody produced in goat affinity isolated antibody, lyophilized powder 價格 V8379 Vitronectin 來源于人類血漿 lyophilized powder, BioReagent, suitable for cell culture 價格 W2266 Anti-Wnt-4 antibody produced in goat affinity isolated antibody, lyophilized powder 價格 P7280 多聚-D-賴氨酸 氫溴酸鹽 average mol wt 30,000-70,000, lyophilized powder, γ-irradiated, BioReagent, suitable for cell culture 價格 P6407 多聚-D-賴氨酸 氫溴酸鹽 mol wt 70,000-150,000, lyophilized powder, γ-irradiated, BioReagent, suitable for cell culture 價格 L2020 層粘蛋白 來源于 Engelbreth-Holm-Swarm 小鼠肉瘤基底膜 1-2 mg/mL in Tris buffered NaCl, 0.2 μm filtered, BioReagent, suitable for cell culture 價格 L6274 層粘蛋白 來源于人類胎盤 liquid, BioReagent, suitable for cell culture 價格 C4116 環(huán)巴胺 水合物 ≥98% (HPLC) C27H41NO2 · xH2O 價格 F2006 Fibronectin human plasma 纖連蛋白 溶液 來源于人類成纖維細(xì)胞 lyophilized powder, BioReagent, suitable for cell culture 價格 F0895 Fibronectin human plasma 纖連蛋白 溶液 來源于人類成纖維細(xì)胞 liquid, 0.1% (Solution), BioReagent, suitable for cell culture 價格 F0635 Fibronectin rat plasma 纖連蛋白 溶液 來源于人類成纖維細(xì)胞 powder, BioReagent, suitable for cell culture 價格 P9155 聚-L-賴氨酸 氫溴酸鹽 mol wt 30,000-70,000, lyophilized powder, γ-irradiated, BioXtra, suitable for cell culture 價格 P6282 聚-L-賴氨酸 氫溴酸鹽 mol wt 70,000-150,000, lyophilized powder, γ-irradiated, BioXtra, suitable for cell culture 價格 P5899 聚-L-賴氨酸 氫溴酸鹽 mol wt ≥300,000, lyophilized powder, γ-irradiated, BioXtra, suitable for cell culture 價格 P4957 聚-L-鳥氨酸 溶液 mol wt 30,000-70,000, 0.01%, sterile-filtered, BioReagent, suitable for cell culture 價格 C5533 膠原 來源于人類胎盤 Bornstein and Traub Type IV, powder, BioReagent, suitable for cell culture 價格 C7661 膠原 來源于大鼠尾 Bornstein and Traub Type I, powder, BioReagent, suitable for cell culture 價格

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