Mapping bone marrow niches of disseminated tumor cells

Breast cancer cells may disseminate early, before tumor diagnosis. Disseminated tumor cells, or DTCs, reside in the bone marrow, and may persist for years or even decades. Some of these cells may be re-activated to resume aggressive growth, and eventually become overt bone metastases. Recent studies have begun to shed light on this complicated process and revealed multiple steps and intermediate states of colonizing DTCs. However, how cancer-host interactions evolve during this process needs to be further understood. Most of our current knowledge of the bone microenvironment is obtained through studies looking for the hematopoietic stem cell(HSC) niche. Although this long-standing question has not yet been resolved, our search for the HSC niche has resulted in a detailed map of various cell types in the bone marrow. Furthermore, various techniques used to find the HSC niche may also be adapted for finding the cancer cell niche. In this article, we will review the recent progress in both the DTC and HSC areas with a focus on their potential microenvironment niches. We will also discuss how to apply what we have learned from HSC studies to map DTCs in the bone context. We hope to stimulate thoughts and ideas to further elucidate the bone colonization process, and develop potential therapeutic interventions.

FGF13 suppresses acute myeloid leukemia by regulating bone marrow niches

Fibroblast growth factor 13(FGF13)is aberrantly expressed in multiple cancer types,suggesting its essential role in tumorigenesis.Hence,we aimed to explore its definite role in the development of acute myeloid leukemia(AML)and emphasize its associations with bone marrow niches.Results showed that FGF13 was lowly expressed in patients with AML and that its elevated expression was related to prolonged overall survival(OS).Univariate and multivariate Cox regression analyses identified FGF13 as an independent prognostic factor.A prognostic nomogram integrating FGF13 and clinicopathologic variables was constructed to predict 1-,3-,and 5-year OS.Gene mutation and functional analyses indicated that FGF13 was not associated with AML driver mutations but was related to bone marrow niches.As for immunity,FGF13 was remarkably associated with T cell count,immune checkpoint genes,and cytokines.In addition,FGF13 overexpression substantially inhibited the growth and significantly induced the early apoptosis of AML cells.The xenograft study indicated that FGF13 overexpression prolonged the survival of recipient mice.Overall,FGF13 could serve as an independent prognostic factor for AML,and it was closely related to the bone marrow microenvironment.

Bone marrow niches in myelodysplastic syndromes

Genetic and epigenetic lesions within hematopoietic cell populations drive diverse hematological malignancies.Myelodysplastic syndromes(MDS)are a group of myeloid neoplasms affecting the hematopoietic stem cells characterized by recurrent genetic abnormalities,myelodysplasia(a pathological definition of abnormal bone marrow structure),ineffective hematopoiesis resulting in blood cytopenia,and a propensity to evolve into acute myelogenous leukemia.Although there is evidence that the accumulation of a set of genetic mutations is an essential event in MDS,there is an increased appreciation of the contribution of specific microenvironments,niches,in the pathogenesis of MDS and response to treatment.In physiologic hematopoiesis,niches are critical functional units that maintain hematopoietic stem and progenitor cells and regulate their maturation into mature blood cells.In MDS and other hematological malignancies,altered bone marrow niches can promote the survival and expansion of mutant hematopoietic clones and provide a shield from therapy.In this review,we focus on our understanding of the composition and function of hematopoietic niches and their role in the evolution of myeloid malignancies,with an emphasis on MDS.

Preliminary delivery efficiency prediction of nanotherapeutics into crucial cell populations in bone marrow niche

Several crucial stromal cell populations regulate hematopoiesis and malignant diseases in bone marrow niches.Precise regulation of these cell types can remodel niches and develop new therapeutics.Multiple nanocarriers have been developed to transport drugs into the bone marrow selectively.However,the delivery efficiency of these nanotherapeutics into crucial niche cells is still unknown,and there is no method available for predicting delivery efficiency in these cell types.Here,we constructed a three-dimensional bone marrow niche composed of three crucial cell populations:endothelial cells(ECs),mesenchymal stromal cells(MSCs),and osteoblasts(OBs).Mimetic niches were used to detect the cellular uptake of three typical drug nanocarriers into ECs/MSCs/OBs in vitro.Less than 5%of nanocarriers were taken up by three stromal cell types,and most of themwere located in the extracellular matrix.Delivery efficiency in sinusoidal ECs,arteriole ECs,MSCs,and OBs in vivo was analyzed.The correlation analysis showed that the cellular uptake of three nanocarriers in crucial cell types in vitro is positively linear correlated with its delivery efficiency in vivo.The delivery efficiency into MSCs was remarkably higher than that into ECs and OBs,no matterwhat kind of nanocarrier.The overall efficiency into sinusoidal ECswas greatly lower than that into arteriole ECs.All nanocarriers were hard to be delivered into OBs(<1%).Our findings revealed that cell tropisms of nanocarriers with different compositions and ligand attachments in vivo could be predicted via detecting their cellular uptake in bone marrow niches in vitro.This study provided the methodology for niche-directed nanotherapeutics development.

Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis:Implications for bone health

BACKGROUND Osteoporosis(OP)has become a major public health problem worldwide.Most OP treatments are based on the inhibition of bone resorption,and it is necessary to identify additional treatments aimed at enhancing osteogenesis.In the bone marrow(BM)niche,bone mesenchymal stem cells(BMSCs)are exposed to a hypoxic environment.Recently,a few studies have demonstrated that hypoxiainducible factor 2alpha(HIF-2α)is involved in BMSC osteogenic differentiation,but the molecular mechanism involved has not been determined.AIM To investigate the effect of HIF-2αon the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells(HSCs)in the BM niche on the progression of OP.METHODS Mice with BMSC-specific HIF-2αknockout(Prx1-Cre;Hif-2αfl/fl mice)were used for in vivo experiments.Bone quantification was performed on mice of two genotypes with three interventions:Bilateral ovariectomy,semilethal irradiation,and dexamethasone treatment.Moreover,the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes.In vitro,the HIF-2αagonist roxadustat and the HIF-2αinhibitor PT2399 were used to investigate the function of HIF-2αin BMSC osteogenic and adipogenic differentiation.Finally,we investigated the effect of HIF-2αon BMSCs via treatment with the mechanistic target of rapamycin(mTOR)agonist MHY1485 and the mTOR inhibitor rapamycin.RESULTS The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions.In vitro,Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2αagonist roxadustat,and after 7 d of BMSC adipogenic differentiation,the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased;in addition,after 14 d of osteogenic differentiation,BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes.The opposite effects were shown for mouse BMSCs treated with the HIF-2αinhibitor PT2399.The mTOR inhibitor rapamycin was used to confirm that HIF-2αregulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway.Consequently,there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice.CONCLUSION Our study showed that inhibition of HIF-2αdecreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.

Hematopoietic stem cell metabolism and stemness

Hematopoietic stem cells(HSCs)are considered to originate from the aorta-gonad-mesonephros,migrate into fetal liver for a rapid expansion,and eventually reside into a unique hypoxic bone marrow niche,where they maintain their homeostasis throughout their life span.HSCs have been widely used for the treatment of many begin or malignant hematopoietic disorders.However,the unavailability of sufficient amount of HSCs still impedes their applications in the clinic.It is urgent to understand how HSC stemness or cell fates are determined at different developmental stages.Although many intrinsic and extrinsic factors(niche components)have been identified in the regulation of HSC origination,expansion,migration,and localization,the underlying mechanisms remain largely unknown.In this article,we summarize current views on the metabolic profiles of HSCs and related regulatory networks,which shows that intrinsic metabolic regulation may be critical for the cell fate determinations of HSCs:HSCs utilize glycolysis as their major energy sources;mitochondrial respiration is also required for the homeostasis of HSCs;amino acids,lipids,or other nutrient metabolisms also have unique roles in sustaining HSC activities.Mechanistically,many important regulatory pathways,such as MEIS1/HIF1A,MYC,PPM1K/CDC20,and ROS signals,are identified to fine-tune the nutrient metabolisms and cell fate commitments in HSCs.Nevertheless,more effort is required for the optimization or establishment of sensitive and specific metabolic techniques/systems for the metabolism studies in HSCs with limited cell numbers and exploring the metabolic profiles and fundamental regulatory mechanisms of different types of nutrients at each developmental stage of HSCs.