Lipids and cholesterol in particular, have long been associated with breast cancer (BC) onset and progression. However, the causative effects of elevated lipid levels and breast cancer remain largely undisclosed and were the subject of the present study.We took advantage of well-established in vitro and in vivo models of cholesterol enrichment to exploit the mechanism involved in LDL-cholesterol favouring BC growth and invasiveness. We analyzed its effects in models that mimic different BC subtypes and stages.Our data show that LDL-cholesterol (but not HDL-cholesterol) promotes BC cells proliferation, migration and loss of adhesion, hallmarks of the epithelial to mesenchymal transition. In vivo studies modeling cholesterol levels showed that breast tumors are consistently larger and more proliferative in hypercholesterolemic mice, which also have more frequently lung metastases. Microarray analysis revealed an over expression of intermediates of Akt and ERK pathways suggesting a survival response induced by LDL, confirmed by WB analyses. Gene expression analysis also evidenced an activation of ErbB2 signaling pathway and decreased expression of adhesion molecules (cadherin-related family member3, CD226, Claudin 7 and Ocludin) in the cells exposed to LDL.Together, the present work shows novel mechanistic evidence that high LDL-cholesterol levels promote BC progression. These data provide rationale for the clinical control of cholesterol levels in BC patients.

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.Over the last decade, different studies reported EPCs as essential in restoring injured vessels. EPCs belong to a subset of cells, arising from hematopoietic stem cells in bone marrow; upon pro-angiogenic stimuli, they proliferate, migrate, and differentiate into endothelial cells (ECs) [4][5][6]. Some reports addressing EPCs and disease, such as systemic sclerosis, showed contradictory and discrepant results about EPCs mobilization and differentiation; in part, because there is a lack of a precise panel of cell surface markers used for the characterization of this subset of cells [4][5][6][7][8][9][10]. In mouse embryonic vascular endothelium, erythro-myeloid progenitors (EMPs) can differentiate into ECs [11] and in a mouse model of carotid injury, monocytes (CD14 + cells) are capable of improving re-endothelialization [12]. In vivo and in vitro targeting of Tie2-monocytes decreases angiogenesis by abrogating EC proliferation [13][14][15] and an in vivo CCR2 (chemokine (C-C motif) receptor 2) knockout impairs monocytes recruitment and VEGFA (also named VEGF, vascular endothelial growth factor) expression, accompanied by a reduction in the angiogenesis rate [16]. The release of cytokines and pro-angiogenic factors (e.g., VEGFA, VEGFC, and VEGFD, TNFα (tumor necrosis factor α), IL-8 (interleukin-8), and FGF-2 (fibroblast growth factor-2), and extracellular matrix (ECM) modifying proteins (e.g., metalloproteinase-9 (MMP-9)) by macrophages enhances the tissue's ability to support capillary sprouting and vascular density [17,18]. The precise mechanism by which monocytes influence angiogenesis in tissue development, homeostasis, and diseases is not fully understood. However, different studies, have shown that under in vitro pro-angiogenic pressure, blood mononuclear cells can acquire endothelial markers and morphology [19][20][21]. In addition, in a previous study, we showed that some ECs sim...

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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.