Cancer-associated fibroblasts (CAF) comprise the majority of stromal cells in breast cancers, yet their precise origins and relative functional contributions to malignant progression remain uncertain. Local invasion leads to the proximity of cancer cells and adipocytes, which respond by phenotypical changes to generate fibroblast-like cells termed as adipocyte-derived fibroblasts (ADF) here. These cells exhibit enhanced secretion of fibronectin and collagen I, increased migratory/invasive abilities, and increased expression of the CAF marker FSP-1 but not a-SMA. Generation of the ADF phenotype depends on reactivation of the Wnt/b-catenin pathway in response to Wnt3a secreted by tumor cells. Tumor cells cocultivated with ADFs in two-dimensional or spheroid culture display increased invasive capabilities. In clinical specimens of breast cancer, we confirmed the presence of this new stromal subpopulation. By defining a new stromal cell population, our results offer new opportunities for stroma-targeted therapies in breast cancer. Cancer Res; 73(18); 5657-68. Ó2013 AACR.

Highlights d G-CSF is required, but not sufficient, to mobilize immature low-density neutrophils d Immature low-density neutrophils are defined by a C/EBPε transcriptional signature d Immature low-density neutrophils promote the formation of liver metastases d Immature low-density neutrophils have a higher global bioenergetic capacity

Cancer cells must adapt their metabolism to meet the energetic and biosynthetic demands that accompany rapid growth of the primary tumor and colonization of distinct metastatic sites. Different stages of the metastatic cascade can also present distinct metabolic challenges to disseminating cancer cells. However, little is known regarding how changes in cellular metabolism, both within the cancer cell and the metastatic microenvironment, alter the ability of tumor cells to colonize and grow in distinct secondary sites. This review examines the concept of metabolic heterogeneity within the primary tumor, and how cancer cells are metabolically coupled with other cancer cells that comprise the tumor and cells within the tumor stroma. We examine how metabolic strategies, which are engaged by cancer cells in the primary site, change during the metastatic process. Finally, we discuss the metabolic adaptations that occur as cancer cells colonize foreign metastatic microenvironments and how cancer cells influence the metabolism of stromal cells at sites of metastasis. Through a discussion of these topics, it is clear that plasticity in tumor metabolic programs, which allows cancer cells to adapt and grow in hostile microenvironments, is emerging as an important variable that may change clinical approaches to managing metastatic disease. Cancer Res; 76(18); 5201-8. Ó2016 AACR.

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Increasing evidence supports the critical roles played by adipose tissue in breast cancer progression. Yet, the mediators and mechanisms are poorly understood. Here, we show that breast cancer-associated adipose tissue from freshly isolated tumors promotes F-actin remodeling, cellular scattering, invasiveness, and spheroid reorganization of cultured breast cancer cells. A combination of techniques, including transcriptomics, proteomics, and kinomics enabled us to identify paracrine secretion of oncostatin M (OSM) by cancer-associated adipose tissue. Specifically, OSM, expressed by CD45 þ leucocytes in the stromal vascular fraction, induced phosphorylation of STAT3 (pSTAT3-)Y705 and S727 in breast cancer cells and transcription of several STAT3-dependent genes, including S100 family members S100A7, S100A8, and S100A9. Autocrine activation of STAT3 in MCF-7 cells ectopically expressing OSMinduced cellular scattering and peritumoral neovascularization of orthotopic xenografts. Conversely, selective inhibition of OSM by neutralizing antibody and Jak family kinases by tofacitinib inhibited STAT3 signaling, peritumoral angiogenesis, and cellular scattering. Importantly, nuclear staining of pSTAT3-Y705 identified at the tumor invasion front in ductal breast carcinomas correlates with increased lymphovascular invasion. Our work reveals the potential of novel therapeutic strategies targeting the OSM and STAT3 axis in patients with breast cancer harboring nuclear pSTAT3-Y705. Cancer Res; 74(23);

Prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is increasingly believed to play a paracrine role in prostate cancer progression. Our previous work demonstrates that adipocytes promote homing of prostate cancer cells to PPAT and that this effect is upregulated by obesity. Here, we show that once tumor cells have invaded PPAT (mimicked by an in vitro model of coculture), they establish a bidirectional crosstalk with adipocytes, which promotes tumor cell invasion. Indeed, tumor cells induce adipocyte lipolysis and the free fatty acids (FFA) released are taken up and stored by tumor cells. Incubation with exogenous lipids also stimulates tumor cell invasion, underlining the importance of lipid transfer in prostate cancer aggressiveness. Transferred FFAs (after coculture or exogenous lipid treatment) stimulate the expression of one isoform of the pro-oxidant enzyme NADPH oxidase, NOX5. NOX5 increases intracellular reactive oxygen species (ROS) that, in turn, activate a HIF1/MMP14 pathway, which is responsible for the increased tumor cell invasion. In obesity, tumor-surrounding adipocytes are more prone to activate the depicted signaling pathway and to induce tumor invasion. Finally, the expression of NOX5 and MMP14 is upregulated at the invasive front of human tumors where cancer cells are in close proximity to adipocytes and this process is amplified in obese patients, underlining the clinical relevance of our results. Implications: Our work emphasizes the key role of adjacent PPAT in prostate cancer dissemination and proposes new molecular targets for the treatment of obese patients exhibiting aggressive diseases.

IntroductionClinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated.MethodsWe used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer.ResultsAdipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases.ConclusionsCollectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1088-6) contains supplementary material, which is available to authorized users.

Highlights d Kinase inhibitors (KIs) and biguanides synergistically target cancer cells d mTORC1/4E-BP axis regulates aspartate, asparagine, and serine biosynthetic enzymes d 4E-BPs and HIF-1a determine responses to KI/biguanide combinations d Cancer cell metabolic plasticity limits efficacy of the KI/ biguanide combinations