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WJCR

World Journal of Cancer Research

2164-9049

Scientific Research Publishing

10.12677/WJCR.2022.123022

WJCR-53892

WJCR20220300000_22471217.pdf

医药卫生

VEGF、脂肪因子与结直肠癌发病相关机制的研究进展 Research Progress of VEGF, Adipokine and the Pathogenesis of Colorectal Cancer

成

文

¹ ²

null

昆明理工大学医学院，云南昆明

16 05 2022

12 03 161 166

2014

This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

结直肠癌作为一种新发病例及死亡病例均在全世界排名前列的癌症，其发病机制尚需深入研究。血管内皮细胞生长因子能促进新生血管的生成，在肿瘤增殖、侵袭和迁移过程中起到重要作用。脂肪因子包括瘦素、脂联素、网膜素、细胞因子等，这些脂肪因子与结直肠癌的发生发展密切相关。本文就结直肠癌发生发展进程与血管内皮细胞生长因子及脂肪因子之间的关系及血管内皮细胞生长与脂肪因子之间的联系进行综述，期望为防治结直肠癌提供积极的理论依据。 Colorectal cancer is a cancer with a high incidence of new cases and deaths in the world, and its pathogenesis needs to be further studied. Vascular endothelial cell growth factor can promote the formation of new blood vessels and play an important role in the process of tumor proliferation, invasion and migration. Adipokines include leptin, adiponectin, retinin and cytokines, and these adipokines are closely related to the occurrence and development of colorectal cancer. This paper reviews the relationship between the occurrence and development of colorectal cancer and vascular endothelial cell growth factor and adipokine as well as the relationship between vascular endothelial cell growth factor and adipokine, hoping to provide a positive theoretical basis for the prevention and treatment of colorectal cancer.

结直肠癌、血管内皮细胞生长因子、脂肪因子, Colorectal Cancer Vascular Endothelial Cell Growth Factor Adipokine

摘要

关键词

结直肠癌、血管内皮细胞生长因子、脂肪因子

Research Progress of VEGF, Adipokine and the Pathogenesis of Colorectal Cancer<sup> </sup>

Wen Cheng

School of Medicine, Kunming University of Science and Technology, Kunming Yunnan

Received: Jun. 28^th, 2022; accepted: Jul. 9^th, 2022; published: Jul. 21^st, 2022

ABSTRACT

Colorectal cancer is a cancer with a high incidence of new cases and deaths in the world, and its pathogenesis needs to be further studied. Vascular endothelial cell growth factor can promote the formation of new blood vessels and play an important role in the process of tumor proliferation, invasion and migration. Adipokines include leptin, adiponectin, retinin and cytokines, and these adipokines are closely related to the occurrence and development of colorectal cancer. This paper reviews the relationship between the occurrence and development of colorectal cancer and vascular endothelial cell growth factor and adipokine as well as the relationship between vascular endothelial cell growth factor and adipokine, hoping to provide a positive theoretical basis for the prevention and treatment of colorectal cancer.

Keywords:Colorectal Cancer, Vascular Endothelial Cell Growth Factor, Adipokine

This work is licensed under the Creative Commons Attribution-NonCommercial International License (CC BY-NC 4.0).

http://creativecommons.org/licenses/by-nc/4.0/

1. 引言

结直肠癌(carcinoma of colon and rectum)是一种肠道中常见的癌症，是指大肠粘膜上皮在环境或遗传等多种致癌因素作用下发生的恶性肿瘤。迄今为止尚未知晓其发病机制，流行病学研究显示其风险因素包括年龄、性别、遗传、肥胖等。此类疾病预后较差，死亡率较高，其新发病例及死亡病例均在全世界排名前列，在消化系统癌症中仅次于胃癌 [ 1 ]。因此如何有效的防治结直肠癌是我们面临的重大挑战。

血管内皮细胞生长因子(vascular endothelial growth factor, VEGF)在肿瘤的生长和侵袭中起到至关重要的作用 [ 2 ] [ 3 ] [ 4 ] [ 5 ]。脂肪因子(adipokines)是脂肪细胞分泌的细胞因子，包括瘦素(leptin, LP)、脂联素(adiponectin, ADPN)、网膜素(omentin)、细胞因子(cytokine, CK)等。这些脂肪因子与肿瘤的发生密切相关。

2. 血管内皮生长因子与结直肠癌

VEGF及其受体酪氨酸激酶(receptor tyrosine kinase, RTK)是重要的促血管生成因子，在肿瘤侵袭和迁移中起到重要作用。体内高表达VEGF的结直肠癌患者肿瘤复发率高，生存期短 [ 6 ]。

VEGF的减少降低酪氨酸磷酸酶的活性，抑制了多种信号蛋白的激活，进而影响癌细胞的生存和繁殖 [ 7 ]。VEGF家族包括六大成员，表达最广泛，含量最高的是VEGF-A，文献中常常提及的VEGF就是指VEGF-A。VEGF和特异性受体(VEGFR)结合后才能发挥生物学功能。VEGFR家族包括5种，其中VEGFR-2是介导VEGF促血管生成作用的主要受体。VEGFR-2是一种跨膜蛋白，主要分布在血管内皮细胞上，其胞内区域含有酪氨酸激酶结构域。大多数肿瘤细胞表面高表达VEGF，可能与原癌基因的异常激活及抑癌基因的失活有关。缺氧条件下VEGF的表达也会上调。VEGF不仅能以旁分泌和自分泌的方式作用于内皮细胞，它在结直肠癌细胞中还具有胞内作用 [ 7 ]。

VEGF-VEGF-2促血管生成机制如下：VEGF与VEGFR-2结合后，VEGFR-2受体二聚体化，胞内段酪氨酸残基磷酸化，进而活化磷脂酶C (phospholipase C, PLC)，引起蛋白激酶C (Protein Kinase C, PKC)途径活化，产生三磷酸肌醇(inositol triphosphate, IP3)，并动员细胞内钙离子。其中PKC也能活化PKC-RAF-MEK-MAPK激酶途径。研究表明，VEGF对结直肠癌生存的影响主要通过AKT介导的信号通路 [ 8 ]。

由于血管细胞生成因子在肿瘤血管生成中具有重要作用，科学家研制出抑制VEGF/VEGFR信号通路的药物贝伐单抗(bevacizumab)，发挥抗血管生成作用，防治肿瘤。

近来有研究发现Regorafenib (瑞格菲尼)能通过抑制旁分泌和自分泌VEGF信号通路的转导抑制肿瘤 [ 9 ]。对肿瘤来说，抑制血管生长因子受体明显激活了肿瘤的迁移能力；在结直肠癌细胞中抑制自分泌和旁分泌VEGF/VEGFR信号通路能诱导恶性细胞表型 [ 9 ]。相比而言，阻断肿瘤血管生成中的另外两种信号通路受体FGG-R和PDGF-R则抑制恶性表型的产生 [ 10 ] [ 11 ]。当药物作用于内皮细胞时，明显抑制肿瘤细胞的血管生成，导致肿瘤的消退。相反，当抑制剂作用于肿瘤细胞(肿瘤细胞表面也存在VEGFR)时，肿瘤细胞的迁移能力和致病性增强 [ 12 ]。

另一项研究发现结直肠癌细胞中VEGF的缺失降低了细胞存活率，增强了细胞的化学敏感性；VEGFR-1的减少降低了结直肠癌细胞中磷酸化蛋白激酶B (pAKT)的水平；VEGF的缺失降低细胞内蛋白激酶B (AKT)的分子活性，而且这种途径与VEGFR的作用无关，但是能被酪氨酸磷酸酶抑制剂所挽救 [ 7 ]。

在结直肠癌临床治疗中发现抗VEGF的治疗药物尚未达到预期效果，进一步研究VEGF的机制，研发对癌细胞具有显著疗效的药物对提高肿瘤患者存活率有着积极影响。

3. 脂肪因子 3.1. 瘦素与结直肠癌

人类瘦素基因也被称之为ob基因，编码167个氨基酸组成的长度为16kda的瘦素蛋白 [ 13 ]。瘦素的主要功能是调节食物摄入和能量消耗，作用靶点不仅仅是脂肪组织，还包括中枢神经系统、肝脏和肌肉组织。

瘦素的循环水平升高与结直肠癌等癌症相关。高表达的瘦素会能促进血管的生成，辅助肿瘤细胞的侵袭及迁移 [ 14 ]。瘦素还能增加抗凋亡蛋白、炎症因子的表达 [ 15 ] [ 16 ]。

瘦素与瘦素受体结合后会诱导JAK2 (非受体型酪氨酸蛋白激酶)磷酸化位于胞内结构域的酪氨酸，JAK2被激活后，多个信号通路会被激活，包括STAT3，MAPK，PI3K，ERK1/2，AMPK等信号通路 [ 17 ] [ 18 ]，它们可以调节基因的表达，比如上调参与细胞周期、抗凋亡、促进细胞侵袭、促血管生成和炎症反应的基因 [ 19 ]，促进结直肠癌的扩散和转移。

因此瘦素及瘦素受体可以作为药物靶标，用以研制新型药物以改善患者的预后。

3.2. 脂联素

脂联素是一种与脂肪质量成反比的激素，它由AdipoQ基因编码，翻译产生30 KDa的蛋白质，长度为244个氨基酸。脂联素是已知的结肠癌发展的介质，这种蛋白在脂肪细胞分化的早期和晚期发挥负调控的作用 [ 20 ]。缺乏脂联素会导致肠道息肉的增长，引发结直肠癌 [ 20 ]，低脂联素水平与结直肠癌分期有关，提示低脂联素水平可能与预后不良及癌症的发生有关 [ 21 ]。低脂联素水平可能通过合成代谢激素和促炎因子促进肿瘤增殖 [ 22 ]。这表明，临床治疗时可以通过提高脂联素水平调节结直肠癌病人的不良预后。此外，脂联素与腺瘤数量呈显著性负相关，可以作为结直肠肿瘤的良好生物标志物 [ 20 ]。

有研究表明脂联素不仅能够促进细胞周期素依赖性激酶抑制因子p 21/p 27表达，抑制细胞周期的进行从而抑制癌细胞的增殖，还能通过氧化应激反应诱导结直肠癌细胞凋亡 [ 23 ] [ 24 ]。

因此高水平的脂联素对结直肠癌患者的治疗以及预后有积极作用。

3.3. 网膜素-1与结直肠癌

网膜素-1是在网膜脂肪组织中发现的一种由313个氨基酸组成的脂肪因子，作为一种内分泌因子调节全身的代谢，在局部以旁分泌和自分泌的方式发挥作用 [ 18 ]。在正常人体中，网膜素-1循环血含量较高，但在肥胖患者体内显著降低，并且网膜素-1水平与肥胖呈负相关 [ 18 ]。而肥胖也是造成结直肠癌的风险因素之一。高水平的网膜素-1对结直肠癌干细胞具有抑制增殖，促进凋亡的作用，网膜素-1的这种作用机制可能与抑制AKt通路有关 [ 25 ]。

因此维持体内高水平的网膜素对结直肠癌患者的治疗以及预后有积极作用。

3.4. 细胞因子与结直肠癌

细胞因子是免疫原、丝裂原或其他刺激剂诱导多种细胞产生的低分子量可溶性蛋白质，可分为白介素、干扰素、趋化因子、肿瘤坏死因子超家族、集落刺激因子、生长因子等六类，在癌症的发病机制中。细胞因子主要通过对炎症的调节影响癌症的发生发展。细胞因子主要是通过NF-kB分子与癌症相联系。NF-kB是一种转录因子，能在炎症因子(如IL-6、TNF-α和IL-1B)、生长因子、细菌和病毒等多种刺激下被激活。NF-kB又与细胞增殖、血管生成、转移与凋亡有关 [ 26 ]。NF-kB主要通过调节IL-6 (白介素-6)进行信号转导，而IL-6与结直肠癌的发生发展相关 [ 27 ]，因此NF-kB也与结直肠癌有关。NF-kB有激活抗凋亡基因表达的能力，这种基因表达可以阻止由多种炎症细胞因子诱导的凋亡过程 [ 28 ]。NF-kB对肿瘤的作用具有两面性，一方面它可以抑制肿瘤的生长，在人体抑癌基因p53介导的凋亡过程中发挥作用；另一方面又会促进肿瘤的生长，能增强肿瘤的转移。因此我们需要通过某种机制使得细胞内的NF-kB信号转导途径中抑癌途径开放，促癌途径关闭，达到防治肿瘤的目的。

4. VEGF、脂肪因子在结直肠癌发生发展中的相互作用

VEGF在结直肠癌中主要起到促血管生成的作用，主要通过三种信号转导途径进行信号的传递，包括PI3K-Akt (磷脂酰肌醇3-激酶-蛋白激酶B)信号途径、NF-kB信号途径、MAPK (丝裂原活化蛋白激酶)信号途径等。瘦素水平的升高激活了JAK2通路和PI3K/AKt通路，这两条通路的联合激活促进了上皮细胞的侵袭性。Ogunwobi和Beales报道瘦素通过激活表皮生长因子受体系统来刺激增殖 [ 29 ] [ 30 ]。脂联素激活的AMP活化蛋白激酶(AMPK)可通过蛋白磷酸酶2A (PP2A)拮抗瘦素诱导的PI3K/AKt通路的激活。脂联素能拮抗瘦素，而脂联素的降低有望通过拮抗作用的降低进一步促进瘦素信号传递 [ 29 ] [ 30 ] [ 31 ]。

Omentin参与活化Akt信号通路，Akt的下游靶点内皮一氧化氮合酶(eNOS)也参与结直肠癌的发生。研究表明AKt活化通过增强细胞增殖活性和阻断凋亡在结直肠癌的进展过程中发挥重要作用。可以推测，omentin通过促进Akt信号通路的激活，进而调控eNOS，可能是结直肠癌的发病机制之一。Akt激酶可调节血管通透性、血管生成反应以及后续的血管成熟 [ 32 ] [ 33 ]。

细胞因子对VEGF的表达有调节作用。白介素-33 (IL-33)表达的增加促进肿瘤生长和血管生成，IL-33可能通过作为核因子激活NF-kB和MAPK信号通路，促进肿瘤生长，增强增殖 [ 34 ]。

因此我们可以推测瘦素与omentin可以通过激活PI3K/AKt通路提高VEGF表达水平，脂联素可以通过抑制PI3K/AKt通路降低VEGF表达水平，细胞因子可以通过激活NF-kB和MAPK等信号通路调节VEGF表达。

因此脂肪因子与VEGF之间存在着内在联系，有些脂肪因子和VAGE具有协同作用，而另一些则是拮抗作用，但是其具体机制还需要更加深入的了解。

5. 小结与展望

VEGF与脂肪因子对结直肠癌的发生发展过程起着重要作用。在结直肠肿瘤细胞中VEGF的转导机制是极其复杂的，但抗VEGF治疗的效果并不像预期的一样好。因此进一步探究结直肠癌的发病机理，明确VEGF信号转导机制，了解VEGF与脂肪因子之间的相互作用，阐明二者与结直肠癌之间发生发展的机制，以期找到与结直肠癌发生、转移和侵袭有关的关键性靶点或者可行的联合治疗方法，为防治结直肠癌提供积极的理论依据。

文章引用

成文. VEGF、脂肪因子与结直肠癌发病相关机制的研究进展Research Progress of VEGF, Adipokine and the Pathogenesis of Colorectal Cancer[J]. 世界肿瘤研究, 2022, 12(03): 161-166. https://doi.org/10.12677/WJCR.2022.123022

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