NDLI: STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Silva, Lidia Santos Goncalves, Luis Gafeira Silva, Fernanda Domingues, Germana Maximo, Valdemar Ferreira, Joana Lam, Eric W-F Dias, Sergio Felix, Ana Serpa, Jacinta
Description	Country affiliation: Portugal Author Affiliation: Silva LS ( Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.); Goncalves LG ( Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal.); Silva F ( Instituto de Tecnologia Quimica e Biológica (ITQB) António Xavier, Universidade NOVA, Oeiras, Portugal.); Domingues G ( Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.); Maximo V ( Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal.); Ferreira J ( Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.); Lam EW ( Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal.); Dias S ( Medical Faculty, University of Porto, Porto, Portugal.); Felix A ( Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.); Serpa J ( Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), 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 cervix 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 with MCT1 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.
File Format	HTM / HTML
ISSN	10104283
Issue Number	4
Journal	Tumor Biology
Volume Number	37
e-ISSN	14230380
Language	English
Publisher	Springer
Publisher Date	2016-04-01
Publisher Place	Netherlands
Access Restriction	Subscribed
Content Type	Text
Resource Type	Article
Subject	Medicine Cancer Research

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