Cancer metabolic profiles point out new therapeutic targets

Our study reinforces the role of the microenvironment in the metabolic adaptation of cancer cells, showing that cells that retain metabolic features of their normal counterparts are positively selected by the organ’s microenvironment. In uterine cervix cancer, monocarboxylates transporter 1 (MCT1) was shown to be a key element in squamous cell carcinoma (the prevalent histological type) development. The expression of MCT1 enables cancer cells to consume lactic acid present in cervico-vaginal microenvironment. We believe MCT1 is a suitable therapeutic target in uterine cervix cancer.

Authors and Affiliations:

Lidia Santos Silva^1,2,  Luis Gafeira Goncalves³,  Fernanda Silva^1,2, Germana Domingues^1,2 ,  Valdemar Maximo^4,5,  Joana Ferreira², EricW.-F. Lam⁶, Sergio Dias⁷,  Ana Felix^1,2,  Jacinta Serpa^1,2

¹- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal

²- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal

³- Instituto de Tecnologia Quimica e Biológica (ITQB) António Xavier, Universidade NOVA, Oeiras, Portugal

⁴- Medical Faculty, University of Porto, Porto, Portugal

⁵- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

⁶- Department of Surgery and Cancer, Imperial College London, London, UK

⁷- Instituto de Medicina Molecular da Universidade de Lisboa, Lisbon, Portugal

Abstract:

Uterine cervix cancer is the second most common malignancy in women worldwide with human papillomavirus (HPV) as the etiologic factor. The two main histological variants, squamous cell carcinomas (SCC) and adenocarcinomas (AC), resemble the cell morphology of exocervix and endocervix, respectively. Cancer metabolism is a cancer Hallmark conditioned by the microenvironment. As uterine cérvix homeostasis is dependent on lactate, we hypothesized lactate plays a role in uterine cervix cancer progression. Using in vitro (SiHa-SCC and HeLa-AC) and BALB-c/SCID models, we demonstrated that lactate metabolism is linked to histological types, with SCC predominantly consuming and AC producing lactate. MCT1 is a key factor, allowing lactate consumption and being regulated in vitro by lactate through the FOXM1:STAT3 pathway. In vivo models showed that SCC (SiHa) expresses MCT1 and is dependent on lactate to grow, whereas AC (HeLa) expresses MCT1 and MCT4, with

higher growth capacities. Immunohistochemical analysis of tissue microarrays (TMA) from human cervical tumors showed that MCT1 expression associates with the SCC type and metastatic behavior of AC, whereas MCT4 expression concomitantly increases from in situ SCC to invasive SCC and is significantly associated with the AC type. Consistently, FOXM1 expression is statistically associated withMCT1 positivity in SCC, whereas the expression of FOXO3a, a FOXM1 functional antagonist, is linked to MCT1 negativity in AC. 

Our study reinforces the role of the microenvironment in the metabolic adaptation of cancer cells, showing that cells that retain metabolic features of their normal counterparts are positively selected by the organ’s microenvironment and will survive. In particular, MCT1 was shown to be a key element in uterine cervix cancer development; however, further studies are needed to validate MCT1 as a suitable therapeutic target in uterine cervix cancer.

Journal:

Tumor Biology 12 Nov 2015; DOI 10.1007/s13277-015-4385-z

Link: http://link.springer.com/article/10.1007%2Fs13277-015-4385-z