脂联素与肿瘤相关性的研究进展

脂肪组织已经不是普通意义上的脂肪仓库,而成为一个内分泌器官。脂肪细胞分泌的众多脂肪因子当中,脂联素(adiponectin)是惟一一个随着脂肪组织体积变大在血液循环中浓度反而降低的因子。脂联素不但在糖类和脂类代谢过程中起到重要作用,目前也认为和一些恶性肿瘤有关。大量的临床试验和基础研究表明,肿瘤患者血清脂联素水平偏低,并且肿瘤细胞表达脂联素受体。因此,脂联素可能通过与脂联素受体结合并激活受体和信号传导通路的下游,直接作用于肿瘤细胞,或者通过抗血管生成,诱导肿瘤细胞凋亡和其他机制调节细胞增殖,从而导致肿瘤的发生。通过研究脂联素,可以发现肥胖和肿瘤之间的关系。     

肥胖脂肪因子与食管腺癌的研究进展

肥胖与肿瘤是全球两大影响健康的重要问题,肥胖增加食管腺癌的发病及死亡风险。脂肪组织能够分泌多种生物学活性的脂肪因子,如瘦素、脂联素、抵抗素等。近年研究发现脂肪因子在胃食管返流病、Barrett食管及癌变中发挥重要作用。本文就肥胖及脂肪因子与食管腺癌的研究进展进行综述。     

肥胖与结直肠癌发病机制的研究进展

肥胖是由于机体能量长期供过于求,过多的脂肪在体内堆积所致。近年来,随着人们物质水平的提高以及生活习惯的改变,肥胖人群所占的比例越来越多,并成为结直肠癌发生发展的高危因素。肥胖所致结直肠癌发病机制有多种,包括瘦素、脂联素和炎症因子等脂肪因子的作用,以及胰岛素抵抗、miRNA、微量元素、维生素、氧化应激反应和肠道微生态紊乱等方面的原因。本文对其作用机制的研究进展加以综述,以期对结直肠癌的预防和治疗起到积极的指导作用。     

脂肪因子在肿瘤治疗中的研究进展

肥胖是多种肿瘤发生的高危因素, 在肥胖促进肿瘤发生、发展的过程中, 脂肪组织分泌的脂肪因子扮演着重要的角色。不同的脂肪因子通过其各自的信号通路发挥着促癌或抑癌作用。调整生活方式控制体质量或者靶向脂肪因子及其受体, 是肿瘤治疗领域的一大研究方向, 但目前多数因子还处于基础研究及临床前研究阶段, 有关各种脂肪因子促癌或抑癌的分子机制还待进一步探索, 同时双重抑制剂及联合疗法是未来脂肪因子用于肿瘤治疗的重点研究策略。     

脂联素对肿瘤新生血管的作用

 脂联素是由脂肪组织特异分泌的一种细胞因子,在糖代谢和脂类代谢中起着重要作用,在与肥胖相关恶性肿瘤的发生发展中也起着重要的作用。目前的研究对脂联素对肿瘤血管的作用仍有很大分歧,本文讨论脂联素对肿瘤新生血管的作用,提示其作为肿瘤血管抑制剂的应用前景。     

脂肪因子与结直肠癌

脂联素、瘦素、网膜素、内脂素均为脂肪组织细胞分泌的脂肪因子,与肥胖、胰岛素抵抗密切相关.研究发现上述脂肪因子也与结直肠癌的发生发展密切相关,有望成为结直肠癌临床诊断以及预后判断的生物学标志物.目前关于脂肪因子如何诱发结直肠癌的机制尚不清楚,仍需开展深入的研究.     

Chemerin在代谢综合征相关肿瘤治疗中的作用及机制

代谢综合征是一组以胰岛素抵抗为核心，多种代谢异常簇集发生在同一个体的临床状态，与许多恶性肿瘤的发生有关。脂肪组织可分泌大量脂肪因子，参与代谢综合征及其相关肿瘤的发生发展。Chemerin是近年新确认的脂肪因子，具有促进脂肪分化和炎症反应、影响胰岛素抵抗及调节脂代谢等作用，参与代谢综合征极其相关疾病的进程。此外，作为一种趋化因子，Chemerin可介导肿瘤微环境中多种免疫细胞募集，发挥抗肿瘤作用。本文将针对Chemerin在代谢综合征相关肿瘤治疗中的作用及机制进行综述。     

肥胖与肿瘤的关系：病理生理学及生物学机制

体重增加（超重及肥胖）的特征性表现为慢性高胰岛素血症及胰岛素抵抗,增加肿瘤的发生率及致死率。肥胖能增加多种肿瘤的发病风险,包括常见肿瘤如子宫内膜癌、绝经后乳腺癌、结肠癌、肾癌,以及发病率较低的肿瘤如白血病、多发性骨髓瘤及非何杰金氏淋巴瘤。其病理生理学及生物学机制正渐渐成为研究的热点。其中胰岛素抵抗为其核心机制,此外诸如胰岛素样生长因子、性激素、脂肪素、肥胖相关炎症因子、NF-κB、氧化应急也发挥着重要作用。随着肥胖人口的增加,进一步了解肥胖与肿瘤之间关系,探索出防治肥胖相关性肿瘤的方法,显得愈来愈重要。     

减重手术改善代谢的机制

减重手术是治疗肥胖及相关合并症的有效措施。减重手术改善代谢的机制尚不十分明确。减重术式造成的胃肠 道解剖结构改变是术后代谢改善的基础，通过限制食物摄入、减少食物吸收来降低患者体重、改善代谢。此外，术后胃肠道激 素胰高血糖素样肽‑1、YY肽的分泌增加和生长激素释放肽分泌减少可抑制胃肠道蠕动、消化液分泌减少、摄食减少；术后可引 起胆汁酸的增加和肝肠循环的缩短；术后肠道菌群中的厚壁菌减少、变形菌和拟杆菌增加可引起体内脂肪储备下降、脂肪酸结 构改变；术后脂肪因子瘦素分泌减少导致摄食减少，脂联素分泌增加可改善胰岛素敏感性；术后中枢神经系统的改变可降低食 物奖赏反应活性，减少摄食。以上这些改变均能改善术后的代谢状况。而且减重术后代谢改善的原因不是单一方面的作用， 是相互影响、共同变化的结果。本文就目前关于减重手术改善代谢相关机制的研究进展做简要综述。     

肥胖与肿瘤

肥胖是乳腺癌、大肠癌等多种肿瘤发生的危险因素.研究表明,肥胖通过胰岛素和胰岛素样生长因子-1(IGF-1)、瘦素、脂肪细胞因子、性激素等多种因子影响癌症的发生和发展.研究肥胖与癌症发生发展中的作用及机制将为肿瘤的预防和治疗提供新的思路.     

Ovarian carcinoma develops through multiple modes of chromosomal evolution

Ovarian carcinoma has the highest mortality of all of the gynecologic cancers. The chromosomal changes in this tumor type are highly complex, and the karyotypes typically show severe aneuploidy. Despite the abundance of cytogenetic information, with approximately 400 published karyotypes, very little is known about the mode of karyotypic evolution and the possible presence of cytogenetic pathways related to tumor development. In the present investigation we used 387 ovarian carcinoma karyotypes to identify the most frequent genomic imbalances. Tumor cases were then classified with respect to the presence or absence of these imbalances and statistically analyzed to assess the order of appearance of chromosomal imbalances, as well as possible karyotypic pathways and cytogenetic subtypes. We establish the temporal order by which the different imbalances occur and show that at least two cytogenetic pathways exist, one characterized by +7, +8q, and +12, and one by 6q- and 1q-. We show that ovarian carcinomas develop through at least three phases of karyotypic evolution. At the early stages, Phase I, the karyotypic evolution seems to proceed though step-wise acquisition of changes. The transition to Phase II showed signs of an increased chromosomal instability, most probably caused by extensive telomere crisis and the onset of breakage-fusion-bridge cycles. This process was linked to the presence of imbalances characteristic for the 6q-/1q- pathway. The transition to Phase III involved triploidization and was also linked to the presence of the 6q-/1q- pathway.     

Allelic imbalances on chromosome 20 in human transitional cell carcinoma.

One determinant of the survival time of cancer-bearing patients may be genetic factors. In chemically induced bladder cancers of mice, differences in survival time have been observed among several inbred strains. Genetic analyses of such differences in crosses between C57BL / 6 and NON mice revealed that the survival period is determined by two quantitative trait loci on mouse chromosomes 6 and 2, respectively. We explored the possibility that genetic alterations may be observed in the syntenic conserved chromosomal regions of human transitional cell carcinoma corresponding to mouse chromosomes 6 and 2. Human chromosome 7, containing a region syntenic to mouse chromosome 6, is reported to harbor frequent genetic alterations in bladder cancers. In this study, we investigated 70 human urothelial cancers for possible genetic alterations on human chromosome 20p and 20q containing regions syntenic to mouse chromosome 2. Allelic imbalances were observed in 22 cases (31.4%) on 20p and 18 cases (25.7%) on 20q. Those allelic imbalances, however, did not show a direct correlation with the prognosis of the patients. Higher grade tumors tended to show more frequent imbalances on chromosome 20; however, this tendency was not significant.     

Allelic Imbalances on Chromosome 20 in Human Transitional Cell Carcinoma

One determinant of the survival time of cancer-bearing patients may be genetic factors. In chemically induced bladder cancers of mice, differences in survival time have been observed among several inbred strains. Genetic analyses of such differences in crosses between C57BL/6 and NON mice revealed that the survival period is determined by two quantitative trait loci on mouse chromosomes 6 and 2, respectively. We explored the possibility that genetic alterations may be observed in the syntenic conserved chromosomal regions of human transitional cell carcinoma corresponding to mouse chromosomes 6 and 2. Human chromosome 7, containing a region syntenic to mouse chromosome 6, is reported to harbor frequent genetic alterations in bladder cancers. In this study, we investigated 70 human urothelial cancers for possible genetic alterations on human chromosome 20p and 20q containing regions syntenic to mouse chromosome 2. Allelic imbalances were observed in 22 cases (31.4%) on 20p and 18 cases (25.7%) on 20q. Those allelic imbalances, however, did not show a direct correlation with the prognosis of the patients. Higher grade tumors tended to show more frequent imbalances on chromosome 20; however, this tendency was not significant.     

Connecting mitotic instability and chromosome aberrations in cancer--can telomeres bridge the gap?

Gross mitotic disturbances are often found in malignant tumours, but not until recently have the molecular causes and the genomic consequences of these abnormalities started to become known. One potential source of mitotic instability is chromosomes with dysfunctional telomeres, giving rise to a high rate of chromatin bridges at anaphase. These bridges could lead either to structural chromosome rearrangements through chromatin fragmentation or to whole-chromosome losses through kinetochore-spindle detachment. Statistical meta-analyses have recently revealed that tumours with high rates of anaphase bridging, such as ovarian, head and neck, and pancreatic carcinomas, are characterised by multimodal distributions of genomic imbalances, consistent with a dramatically increased rate of chromosome rearrangements. In contrast, tumours without gross cell division disturbances are characterised by a monotonously decreasing distribution of genomic changes. This distribution follows a power-law, best described by a preferential attachment model in which the tolerance for chromosomal changes increases steadily with tumour growth. Even though many common cancers, such as breast, colorectal, and renal cell carcinomas adhere to this simple power-law dynamics, the underlying molecular mechanisms remain elusive.     

Impact of cytogenetic and genomic aberrations of the kallikrein locus in ovarian cancer

The tissue kallikrein (KLK) genes are a new source for biomarkers in ovarian cancer. However, there has been no systematic analysis of copy number and structural rearrangements related to their protein expression. Chromosomal rearrangements and copy number changes of the KLK region were studied by FISH with protein levels measured by ELISA. Ovarian cancer and cell lines revealed the KLK region was subject to copy number imbalances or involved in unbalanced translocations and were associated with increased protein expression of KLKs 5, 6, 7, 8, 9, 10 and 11. In this initial study, we introduce the potential for long‐range chromosomal effects and copy number as a mechanism for the previously reported aberrant expression of many KLK genes in ovarian cancers.     

Changes in allelic imbalances in locally advanced breast cancers after chemotherapy

In advanced breast cancers, TP53 mutation is highly predictive of complete response to high-dose epirubicin/cyclophosphamide chemotherapy. In these tumours with an altered control of genomic stability, accumulation of chemotherapy-induced genetic alterations may contribute to cell death and account for complete response. To explore the effects of chemotherapy on stability of the tumour genome, allelic profiles were obtained from microdissected tumour samples before and after chemotherapy in 29 unresponsive breast cancers (9 with TP53 mutation). Ninety-four per cent allelic profiles remained unchanged after treatment. Interestingly, 11 profiles (6%) showed important changes after treatment; allelic imbalances significantly increased (four cases) or decreased (seven cases) after chemotherapy in three distinct experiments, two of which using laser microdissected tumour cells. These genetic changes were not linked to the TP53 status, but one tumour showed complete disappearance of TP53-mutated cells in the residual tumour after treatment. Altogether, these observations carry important implications for the clonal evolution of breast cancers treated with DNA-damaging agents, as they point both to the importance of tumour heterogeneity and chemotherapy-driven selection of subclones.     

脂代谢通路及脂代谢异常在癌症中的研究现状

脂质具有多种重要的生物功能,在生物体内具有复杂的代谢通路及多种脂质间的相互转化。脂质代谢异常可引发诸多人类疾病,包括糖尿病、肥胖症、癌症以及神经退行性疾病等。肿瘤的发生发展是一个多机制多因素的复杂的生物学过程,近年来,能量代谢异常在多种癌症研究中日益受到关注。随着脂质组学技术的发展,越来越多的研究表明脂质谱系变化及脂代谢异常在癌症的发生发展过程中扮演着十分重要的作用。本文从脂代谢通路、不同脂类在癌症中的异常代谢及其研究进展这几个方面对脂代谢在癌症发生发展中的作用与研究现状作一综述。     

Chromosomal imbalances associated with anaplastic transformation of follicular thyroid carcinomas

The genetic alterations that underlie the progression of follicular thyroid carcinoma towards anaplasia are still largely uncharacterised. We compared the Comparative Genomic Hybridization (CGH) profiles of 20 follicular (FTCs), 12 poorly differentiated (PDTCs) and seven anaplastic thyroid carcinomas (ATCs), in order to identify the chromosomal imbalances potentially associated with cancer progression. We found: (i) when considering that a 'direct' transformation of FTC towards anaplasia occurs, the defined significantly important alterations were the increase of gains at 3q (P<0.05) and 20q (P<0.01), and the increase of losses at 7q (P<0.05) and Xp (P<0.01); (ii) regarding poorly differentiated carcinomas as an intermediate independent entity in the anaplastic transformation of follicular cancers, evidenced as important alterations towards anaplasia, were the proportional decrease in copy sequences at 7p, 7q, 12q and 13q resulting from the significant decrease of DNA gains at 7p and 12q (P<0.05), and the significant increase of losses at 7q and 13q (P<0.05). These results unveil the chromosomal regions where genes of interest in thyroid anaplastic transformation are to be located, and demonstrate that different gene dosage copy sequence imbalances are associated to the 'direct' pathway of transformation of follicular into anaplastic cancers and to the progressive FTC --> PDTC --> ATC pathway.     

Mechanisms underlying the association between obesity and Hodgkin lymphoma

A solid body of knowledge indicates that overweight and obese subjects are prone to develop cancer, aggressive disease, and death more than their lean counterparts. While obesity has been causally associated with various cancers, only a limited number of studies beheld the link with classical Hodgkin lymphoma (HL). Contemporary meta-analysis and prospective studies confirmed the association of body mass index with HL. Besides epidemiological evidence, excess adiposity is known to influence tumor behavior through adipokines, adipose-derived stem cell migration, and metabolism regulation, and by modulating immunoinflammatory response. Nevertheless, the obesity paradox has been described in few cancers. Considering that adipose tissue is an immunomodulatory organ, and that inflammation is the cornerstone of HL pathophysiology, the rationale for being causally related due to endocrine/paracrine interactions cannot be negligible. In this hypothesis-generating review, we explore the biologically plausible links between excess adiposity and HL in light of recent basic and clinical data, in order to create a basis for understanding the underlying mechanisms and foster applied research. The establishment of an association of excess adiposity with HL will determine public health preventive measures to fight obesity and eventually novel therapeutic approaches in HL patients.