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The project was funded by IPOLFG, EPE, by iNOVA4Health (UID/Multi/04462/2019) a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement and by Fundação para a Ciência eTecnologia (PhD student fellowship: PD/BD/128337/2017). Bone marrow contains endothelial progenitor cells (EPCs) that, upon pro-angiogenic stimuli, migrate and differentiate into endothelial cells (ECs) and contribute to re-endothelialization and neo-vascularization. There are currently no reliable markers to characterize EPCs, leading to their inaccurate identification. In the past, we showed that, in a panel of tumors, some cells on the vessel wall co-expressed CD14 (monocytic marker) and CD31 (EC marker), indicating a putative differentiation route of monocytes into ECs. Herein, we disclosed monocytes as potential EPCs, using in vitro and in vivo models, and also addressed the cancer context. Monocytes acquired the capacity to express ECs markers and were able to be incorporated into blood vessels, contributing to cancer progression, by being incorporated in tumor neo-vasculature. Reactive oxygen species (ROS) push monocytes to EC differentiation, and this phenotype is reverted by cysteine (a scavenger and precursor of glutathione), which indicates that angiogenesis is controlled by the interplay between the oxidative stress and the scavenging capacity of the tumor microenvironment. publishersversion published

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.

Here we hypothesize that systemic cholesterol favors metastasis by increasing blood vessel endothelial permeability. The majority of metastatic dissemination occurs through the hematogenous route and factors that alter blood vessel properties can affect the entry of cancer cells in circulation. It is generally accepted that high levels of systemic cholesterol, in particular low density lipoprotein (LDL), have a negative impact in endothelial function. This has been demonstrated mainly in large arteries but less is known about how LDL affects the microvasculature of different organs. High cholesterol has also been associated with poor prognosis in several cancers. In our lab, using orthotopic mouse models of breast cancer, we were able to show that mice in which increased LDL in circulation is induced by a high cholesterol diet, have more metastasis. Here we also show in an “in vitro” system, that LDL increases endothelial permeability and that this can be reverted by blocking the interaction of LDL with the LDL-receptor. Additionally we observe that this higher endothelial permeability is due to cholesterol enrichment of endothelial cells, as nystatin, a cholesterol sequestering agent is also able to revert the phenotype. Back to “in vivo”, using the same orthotopic breast cancer model, we are able to show that high systemic cholesterol increases the number of circulating cancer cells in the blood. We are now testing the hypothesis of whether this is due to increased permeability of tumor blood vessels or of the vessels surrounding the tumor. Citation Format: Ana Magalhaes, Catarina R. Santos, Germana Domingues, Tãnia Carvalho, Sergio Dias. High systemic cholesterol increases blood vessel endothelial permeability and favors metastasis: Are these events related? [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C24.