Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression.

Cancer cells are embedded within the tissue and interact dynamically with its components during cancer progression. Understanding the contribution of cellular components within the tumor microenvironment is crucial for the success of therapeutic applications. Here, we reveal the presence of perivascular GFAP+/Plp1+ cells within the tumor microenvironment. Using in vivo inducible Cre/loxP mediated systems, we demonstrated that these cells derive from tissue-resident Schwann cells. Genetic ablation of endogenous Schwann cells slowed down tumor growth and angiogenesis. Schwann cell-specific depletion also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of tumor biopsies revealed that increased expression of Schwann cell-related genes within melanoma was associated with improved survival. Collectively, our study suggests that Schwann cells regulate tumor progression, indicating that manipulation of Schwann cells may provide a valuable tool to improve cancer patients' outcomes.

C(3)1-TAg in C57BL/6 J background as a model to study mammary tumor development.

Diagnosis and prognosis of breast cancer is based on disease staging identified through histopathological and molecular biology techniques. Animal models are used to gain mechanistic insights into the development of breast cancer. C(3)1-TAg is a genetically engineered mouse model that develops mammary cancer. However, carcinogenesis caused by this transgene was characterized in the Friend Virus B (FVB) background. As most genetic studies are done in mice with C57BL/6 J background, we aimed to define the histological alterations in C3(1)-TAg C57BL/6 J animals. Our results showed that C3(1)-TAg animals with C57BL/6 J background develop solid-basaloid adenoid cystic carcinomas with increased fibrosis, decreased area of adipocytes, and a high proliferative index, which are triple-negative for progesterone, estrogen, and human epidermal growth factor receptor 2 (HER2) receptors. Our results also revealed that tumor development is slower in the C57BL/6 J background when compared with the FVB strain, providing a better model to study the different stages in breast cancer progression.

Ablation of sensory nerves favours melanoma progression.

The tumour mass is composed not only of heterogeneous neoplastic cells, but also a variety of other components that may affect cancer cells behaviour. The lack of detailed knowledge about all the constituents of the tumour microenvironment restricts the design of effective treatments. Nerves have been reported to contribute to the growth and maintenance of numerous tissues. The effects of sensory innervations on tumour growth remain unclear. Here, by using state-of-the-art techniques, including Cre/loxP technologies, confocal microscopy, in vivo-tracing and chemical denervation, we revealed the presence of sensory nerves infiltrating within the melanoma microenvironment, and affecting cancer progression. Strikingly, melanoma growth in vivo was accelerated following genetic ablation or chemical denervation of sensory nerves. In humans, a retrospective analysis of melanoma patients revealed that increased expression of genes related to sensory nerves in tumours was associated with better clinical outcomes. These findings suggest that sensory innervations counteract melanoma progression. The emerging knowledge from this research provides a novel target in the tumour microenvironment for therapeutic benefit in cancer patients.

Cross-talk between lung cancer and bones results in neutrophils that promote tumor progression.

Lung cancer is the leading cause of cancer mortality around the world. The lack of detailed understanding of the cellular and molecular mechanisms participating in the lung tumor progression restrains the development of efficient treatments. Recently, by using state-of-the-art technologies, including in vivo sophisticated Cre/loxP technologies in combination with lung tumor models, it was revealed that osteoblasts activate neutrophils that promote tumor growth in the lung. Strikingly, genetic ablation of osteoblasts abolished lung tumor progression via interruption of SiglecFhigh-expressing neutrophils supply to the tumor microenvironment. Interestingly, SiglecFhigh neutrophil signature was associated with worse lung adenocarcinoma patients outcome. This study identifies novel cellular targets for lung cancer treatment. Here, we summarize and evaluate recent advances in our understanding of lung tumor microenvironment.

Macrophages Generate Pericytes in the Developing Brain.

Pericytes are defined by their anatomical location encircling blood vessels' walls with their long projections. The exact embryonic sources of cerebral pericytes remain poorly understood, especially because of their recently revealed diversity. Yamamoto et al. (Sci Rep 7(1):3855, 2017) using state-of-the-art techniques, including several transgenic mice models, reveal that a subpopulation of brain pericytes are derived from phagocytic macrophages during vascular development. This work highlights a new possible ancestor of brain pericytes. The emerging knowledge from this research may provide new approaches for the treatment of several neurodevelopmental disorders in the future.

Sympathetic nerve-adipocyte interactions in response to acute stress.

Psychological stress predisposes our body to several disorders. Understanding the cellular and molecular mechanisms involved in the physiological responses to psychological stress is essential for the success of therapeutic applications. New studies show, by using in vivo inducible Cre/loxP-mediated approaches in combination with pharmacological blockage, that sympathetic nerves, activated by psychological stress, induce brown adipocytes to produce IL-6. Strikingly, this cytokine promotes gluconeogenesis in hepatocytes, that results in the decline of tolerance to inflammatory organ damage. The comprehension arising from this research will be crucial for the handling of many inflammatory diseases. Here, we review recent advances in our comprehension of the sympathetic nerve-adipocyte axis in the tissue microenvironment.

Pericytes cross-talks within the tumor microenvironment.

Cancer cells are embedded within the tumor microenvironment and interact dynamically with its components during tumor progression. Understanding the molecular mechanisms by which the tumor microenvironment components communicate is crucial for the success of therapeutic applications. Recent studies show, by using state-of-the-art technologies, including sophisticated in vivo inducible Cre/loxP mediated systems and CRISPR-Cas9 gene editing, that pericytes communicate with cancer cells. The arising knowledge on cross-talks within the tumor microenvironment will be essential for the development of new therapies against cancer. Here, we review recent progress in our understanding of pericytes roles within tumors.

Hematopoietic stem cell stretches and moves in its bone marrow niche.

Hematopoietic stem cells are the most illustrious inhabitants of the bone marrow. Direct visualization of endogenous hematopoietic stem cells in this niche is essential to study their functions. Until recently this was not possible in live animals. Recent studies, using state-of-the-art technologies, including sophisticated in vivo inducible genetic approaches in combination with two-photon laser scanning microscopy, allow the follow-up of endogenous hematopoietic stem cells' behavior in their habitat. Strikingly, the new findings reveal that quiescent hematopoietic stem cells are more mobile than previously thought, and link their retained steady state within the niche to a mobile behavior. The arising knowledge from this research will be critical for the therapy of several hematological diseases. Here, we review recent progress in our understanding of hematopoietic stem cell biology in their niches.

Sensory nerves in the spotlight of the stem cell niche.

Niches are specialized tissue microenvironments that control stem cells functioning. The bone marrow mesenchymal stem cell niche defines a location within the marrow in which mesenchymal stem cells are retained and produce new cells throughout life. Deciphering the signaling mechanisms by which the niche regulates stem cell fate will facilitate the use of these cells for therapy. Recent studies, by using state-of-the-art methodologies, including sophisticated in vivo inducible genetic techniques, such as lineage-tracing Cre/loxP mediated systems, in combination with pharmacological inhibition, provide evidence that sensory neuron is an important component of the bone marrow mesenchymal stem cell niche. Strikingly, knockout of a specific receptor in sensory neurons blocked stem cell function in the bone marrow. The knowledge arising from these discoveries will be crucial for stem cell manipulation in the future. Here, we review recent progress in our understanding of sensory nerves biology in the stem cell niche.

Circulating Nestin-GFP+ Cells Participate in the Pathogenesis of Paracoccidioides brasiliensis in the Lungs.

Multiple infectious diseases lead to impaired lung function. Revealing the cellular mechanisms involved in this impairment is crucial for the understanding of how the lungs shift from a physiologic to a pathologic state in each specific condition. In this context, we explored the pathogenesis of Paracoccidioidomycosis, which affects pulmonary functioning. The presence of cells expressing Nestin-GFP has been reported in different tissues, and their roles as tissue-specific progenitors have been stablished in particular organs. Here, we explored how Nestin-GFP+ cells are affected after lung infection by Paracoccidioides brasiliensis, a model of lung granulomatous inflammation with fibrotic outcome. We used Nestin-GFP transgenic mice, parabiosis surgery, confocal microscopy and flow cytometry to investigate the participation of Nestin-GFP+ cells in Paracoccidioides brasiliensis pathogenesis. We revealed that these cells increase in the lungs post-Paracoccidioides brasiliensis infection, accumulating around granulomas. This increase was due mainly to Nestin-GPF+ cells derived from the blood circulation, not associated to blood vessels, that co-express markers suggestive of hematopoietic cells (Sca-1, CD45 and CXCR4). Therefore, our findings suggest that circulating Nestin-GFP+ cells participate in the Paracoccidioides brasiliensis pathogenesis in the lungs.

Pericyte Plasticity in the Brain.

Cerebral pericytes are perivascular cells that stabilize blood vessels. Little is known about the plasticity of pericytes in the adult brain in vivo. Recently, using state-of-the-art technologies, including two-photon microscopy in combination with sophisticated Cre/loxP in vivo tracing techniques, a novel role of pericytes was revealed in vascular remodeling in the adult brain. Strikingly, after pericyte ablation, neighboring pericytes expand their processes and prevent vascular dilatation. This new knowledge provides insights into pericyte plasticity in the adult brain.

Pericytes in the Premetastatic Niche.

The premetastatic niche formed by primary tumor-derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including in vivo lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. Cancer Res; 78(11); 2779-86. ©2018 AACR.

Endothelial Cells as Precursors for Osteoblasts in the Metastatic Prostate Cancer Bone.

Prostate cancer cells metastasize to the bones, causing ectopic bone formation, which results in fractures and pain. The cellular mechanisms underlying new bone production are unknown. In a recent study, Lin and colleagues, by using state-of-the-art techniques, including prostate cancer mouse models in combination with sophisticated in vivo lineage-tracing technologies, revealed that endothelial cells form osteoblasts induced by prostate cancer metastasis in the bone. Strikingly, genetic deletion of osteorix protein from endothelial cells affected prostate cancer-induced osteogenesis in vivo. Deciphering the osteoblasts origin in the bone microenvironment may result in the development of promising new molecular targets for prostate cancer therapy.

Endothelial cells maintain neural stem cells quiescent in their niche.

Niches are specialized microenvironments that regulate stem cells' activity. The neural stem cell (NSC) niche defines a zone in which NSCs are retained and produce new cells of the nervous system throughout life. Understanding the signaling mechanisms by which the niche controls the NSC fate is crucial for the success of clinical applications. In a recent study, Sato and colleagues, by using state-of-the-art techniques, including sophisticated in vivo lineage-tracing technologies, provide evidence that endothelial amyloid precursor protein (APP) is an important component of the NSC niche. Strikingly, depletion of APP increased NSC proliferation in the subventricular zone, indicating that endothelial cells negatively regulate NSCs' growth. The emerging knowledge from this research will be important for the treatment of several neurological diseases.

Identity of Gli1+ cells in the bone marrow.

Bone marrow fibrosis is a critical component of primary myelofibrosis in which normal bone marrow tissue and blood-forming cells are gradually replaced with scar tissue. The specific cellular and molecular mechanisms that cause bone marrow fibrosis are not understood. A recent study using state-of-the-art techniques, including in vivo lineage tracing, provides evidence that Gli1+ cells are the cells responsible for fibrotic disease in the bone marrow. Strikingly, genetic depletion of Gli1+ cells rescues bone marrow failure and abolishes myelofibrosis. This work introduces a new central cellular target for bone marrow fibrosis. The knowledge that emerges from this research will be important for the treatment of several malignant and nonmalignant disorders.

LepR+ cells dispute hegemony with Gli1+ cells in bone marrow fibrosis.

Bone marrow fibrosis is a reactive process, and a central pathological feature of primary myelofibrosis. Revealing the origin of fibroblastic cells in the bone marrow is crucial, as these cells are considered an ideal, and essential target for anti-fibrotic therapy. In 2 recent studies, Decker et al. (2017) and Schneider et al. (2017), by using state-of-the-art techniques including in vivo lineage-tracing, provide evidence that leptin receptor (LepR)-expressing and Gli1-expressing cells are responsible for fibrotic tissue deposition in the bone marrow. However, what is the relationship between these 2 bone marrow cell populations, and what are their relative contributions to bone marrow fibrosis remain unclear. From a drug development perspective, these works bring new cellular targets for bone marrow fibrosis.