Pinheiro Céline, Garcia Eduardo A, Morais-Santos Filipa, Moreira Marise A R, Almeida Fábio M, Jubé Luiz F, Queiroz Geraldo S, Paula Élbio C, Andreoli Maria A, Villa Luisa L, Longatto-Filho Adhemar, Baltazar Fátima
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4710-057, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
BMC Cancer. 2015 Nov 2;15:835. doi: 10.1186/s12885-015-1842-4.
Deregulation of cellular energetic metabolism was recently pointed out as a hallmark of cancer cells. This deregulation involves a metabolic reprogramming that leads to a high production of lactate. Lactate efflux, besides contributing for the glycolytic flux, also acts in the extracellular matrix, contributing for cancer malignancy, by, among other effects, induction of angiogenesis. However, studies on the interplay between cancer metabolism and angiogenesis are scarce. Therefore, the aim of the present study was to evaluate the metabolic and vascular molecular profiles of cervical adenocarcinomas, their co-expression, and their relation to the clinical and pathological behavior.
The immunohistochemical expression of metabolism-related proteins (MCT1, MCT4, CD147, GLUT1 and CAIX) as well as VEGF family members (VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3) was assessed in a series of 232 cervical adenocarcinomas. The co-expression among proteins was assessed and the expression profiles were associated with patients' clinicopathological parameters.
Among the metabolism-related proteins, MCT4 and CAIX were the most frequently expressed in cervical adenocarcinomas while CD147 was the less frequently expressed protein. Overall, VEGF family members showed a strong and extended expression with VEGF-C and VEGFR-2 as the most frequently expressed and VEGFR-1 as the less expressed member. Co-expression of MCT isoforms with VEGF family members was demonstrated. Finally, MCT4 was associated with parametrial invasion and HPV18 infection, CD147 and GLUT1 with distant metastasis, CAIX with tumor size and HPV18 infection, and VEGFR-1 with local and lymphnode metastasis.
The results herein presented provide additional evidence for a crosstalk between deregulating cellular energetics and inducing angiogenesis. Also, the metabolic remodeling and angiogenic switch are relevant to cancer progression and aggressiveness in adenocarcinomas.
细胞能量代谢失调最近被指出是癌细胞的一个标志。这种失调涉及代谢重编程，导致乳酸大量产生。乳酸外流除了有助于糖酵解通量外，还作用于细胞外基质，通过诱导血管生成等多种作用促进癌症恶性进展。然而，关于癌症代谢与血管生成之间相互作用的研究很少。因此，本研究的目的是评估宫颈腺癌的代谢和血管分子特征、它们的共表达情况以及它们与临床和病理行为的关系。
在一系列232例宫颈腺癌中评估代谢相关蛋白（MCT1、MCT4、CD147、GLUT1和CAIX）以及VEGF家族成员（VEGF-A、VEGF-C、VEGF-D、VEGFR-1、VEGFR-2和VEGFR-3）的免疫组化表达。评估蛋白之间的共表达情况，并将表达谱与患者的临床病理参数相关联。
在代谢相关蛋白中，MCT4和CAIX在宫颈腺癌中表达最频繁，而CD147是表达最少的蛋白。总体而言，VEGF家族成员表现出强烈且广泛的表达，其中VEGF-C和VEGFR-2表达最频繁，VEGFR-1表达最少。证实了MCT异构体与VEGF家族成员的共表达。最后，MCT4与宫旁浸润和HPV18感染相关，CD147和GLUT1与远处转移相关，CAIX与肿瘤大小和HPV18感染相关，VEGFR-1与局部和淋巴结转移相关。
本文呈现的结果为细胞能量调节失控与诱导血管生成之间的相互作用提供了更多证据。此外，代谢重塑和血管生成开关与腺癌的癌症进展和侵袭性相关。
