Carcinoma-associated fibroblasts (CAF) have recently been implicated in important aspects of epithelial solid tumor biology, such as neoplastic progression, tumor growth, angiogenesis, and ...metastasis. However, neither the source of CAFs nor the differences between CAFs and fibroblasts from nonneoplastic tissue have been well defined. In this study, we show that human bone marrow-derived mesenchymal stem cells (hMSCs) exposed to tumor-conditioned medium (TCM) over a prolonged period of time assume a CAF-like myofibroblastic phenotype. More importantly, these cells exhibit functional properties of CAFs, including sustained expression of stromal-derived factor-1 (SDF-1) and the ability to promote tumor cell growth both in vitro and in an in vivo coimplantation model, and expression of myofibroblast markers, including alpha-smooth muscle actin and fibroblast surface protein. hMSCs induced to differentiate to a myofibroblast-like phenotype using 5-azacytidine do not promote tumor cell growth as efficiently as hMSCs cultured in TCM nor do they show increased SDF-1 expression. Furthermore, gene expression profiling revealed similarities between TCM-exposed hMSCs and CAFs. Taken together, these data suggest that hMSCs are a source of CAFs and can be used in the modeling of tumor-stroma interactions. To our knowledge, this is the first report showing that hMSCs become activated and resemble carcinoma-associated myofibroblasts on prolonged exposure to conditioned medium from MDAMB231 human breast cancer cells.
Mesenchymal stem cells (MSCs) exhibit tropism for sites of tissue injury and tumors. However, the influence of the microenvironment on MSC phenotype and localization remains incompletely ...characterized. In this study, we begin to define a macrophage-induced MSC phenotype. These MSCs secrete interleukin-6 (IL-6), CCL5, and interferon gamma-induced protein-10 (CXCL10) and exhibit increased mobility in response to multiple soluble factors produced by macrophages including IL-8, CCL2, and CCL5. The pro-migratory phenotype is dependent on activation of a c-Jun N-terminal kinase (JNK) pathway. This work begins to identify the influence of macrophages on MSC biology. These interactions are likely to play an important role in the tissue inflammatory response and may provide insight into the migratory potential of MSCs in inflammation and tissue injury.
Mesenchymal stem cells (MSCs) migrate to tumors both in vitro and in vivo. Gene expression profiling analysis reveals that stromal cell-derived factor 1 (SDF-1) is significantly upregulated in MSCs ...exposed to tumor cell-conditioned medium, when compared with cells treated with control medium, suggesting that SDF-1 signaling is important in mediating MSC migration. This study investigates downstream signaling during MSC migration in response to tumor cell-conditioned medium and recombinant SDF-1 protein treatments. We observed that both recombinant SDF-1 and tumor cell-conditioned medium were able to activate downstream signaling via signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) as revealed by increased phosphorylation of STAT3 and ERK1/2 in human MSCs (hMSCs). Significant impairment of in vitro migration was observed in the presence of MAPK/ERK kinase (MEK) inhibitor PD98059, whereas two Janus kinase 2 (Jak2) inhibitors completely abolished migration induced by tumor cell-conditioned medium. Impaired MSC migration correlated with decreased levels of phosphorylated STAT3 and ERK1/2, suggesting that SDF-1 stimulation activates Jak2/STAT3 as well as MEK/ERK1/2 signaling, which in turn promotes migration of MSCs toward tumor cells. Furthermore, stimulation of hMSCs with recombinant SDF-1 and tumor cell-conditioned medium also significantly activated the focal adhesion kinases (FAKs) and paxillin, which correlated with reorganization of F-actin filaments in hMSCs. Decreased phosphorylation of FAK and paxillin as well as disruption of cytoskeleton organization was observed following Jak2 and MEK inhibitor treatment. Taken together, our results provide insight into the molecular pathways responsible for MSC migration toward the tumor microenvironment and may provide the molecular basis for modifying MSCs for therapeutic purposes.
Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) ...signaling.
We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma.
A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed.
Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).
Wild-type gastrointestinal stromal tumors (WT GIST) are most frequently characterized by succinate dehydrogenase (SDH) deficiency. Reliable
tumor models have been difficult to develop given the ...downstream metabolic effects of SDH deficiency. Improved tumor modeling approaches are needed to develop effective systemic treatment options for patients with WT GIST.
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Mesenchymal stem cells: flip side of the coin Mishra, Pravin J; Mishra, Prasun J; Glod, John W ...
Cancer research (Chicago, Ill.),
02/2009, Letnik:
69, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Tumor-associated fibroblasts or carcinoma-associated fibroblasts (CAF) play an important role in the growth of epithelial solid tumors. Although the cell type of origin of CAFs has not been ...conclusively established, it has been shown that they may be bone marrow derived. One side of the mesenchymal stem cell (MSC) coin is the well-accepted therapeutic potential of these cells for regenerative and immunomodulatory purposes. The ominous dark side is revealed by the recent work demonstrating that hMSCs may be a source of CAFs. In this review, we discuss the role of stromal cells in the tumor microenvironment and suggest that by exploring the in vitro/in vivo interplay between different cell types within the tumor milieu, strategies for improved tumor therapy can be developed.
is amplified in 20% to 25% of neuroblastoma, and
-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high ...priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified
rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and
-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in
-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in
-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. SIGNIFICANCE: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of
-amplified neuroblastoma.
Many sarcomas contain gene fusions that can be pathogenetic mechanisms and diagnostic markers. In this article we review selected fusion sarcomas and techniques for their detection. CIC-DUX4 fusion ...sarcoma is a round cell tumor now considered an entity separate from Ewing sarcoma with a more aggressive clinical course, occurrence in older age, and predilection to soft tissues. It is composed of larger cells than Ewing sarcoma and often has prominent necrosis. Nuclear DUX4 expression is a promising immuno histochemical marker. BCOR-CCNB3 fusion sarcoma is cyclin B3–positive, usually occurs in bone or soft tissue of children, and may mimic a poorly differentiated synovial sarcoma. EWSR1-NFATC2 sarcoma may present in bone or soft tissue. It is typically composed of small round cells in a trabecular pattern in a myxoid matrix resembling myoepithelioma. ACTB-GLI1 fusion sarcoma may mimic a skin adnexal carcinoma, showing focal expression of epithelial markers and S100 protein. NTRK-fusion sarcomas include, in addition to infantile fibrosarcoma with ETV6-NTRK3 fusion, LMNA-NTRK1 fusion sarcoma, a low-grade spindle cell sarcoma seen in peripheral soft tissues in children and young adults. Methods to detect gene fusions include next-generation sequencing panels, anchored multiplex polymerase chain reaction systems to detect partner for a known fusion gene, and comprehensive RNA sequencing to detect virtually all gene fusions. In situ hybridization testing using probes for both fusion partners can be used as an alternative confirmation technique, especially in the absence of satisfactory RNA yield. In addition, fusion protein–related and other immunohistochemical markers can have a high specificity for fusion sarcomas.
•Gene fusions are pathogenetic factors and diagnostic markers seen in many sarcomas.•Fusion discovery methods are RNA/DNA sequencing, FISH, and anchored multiplex PCR.•Some fusion sarcomas, such as CIC-DUX4, can be detected by immunohistochemistry.•BCOR-CCNB3 sarcoma occurring in children mimics undifferentiated synovial sarcoma.•Other new fusion sarcomas include EWSR1-NFATC2, ACTB-GLI1, and LMNA-NTRK1.
Human mesenchymal stem cells (hMSCs) are bone marrow-derived stromal cells, which play a role in tumor progression. We have shown earlier that breast cancer cells secrete higher levels of ...interleukin-6 (IL-6) under hypoxia, leading to the recruitment of hMSCs towards hypoxic tumor cells. We found that (i) MDA-MB-231 cells secrete significantly higher levels of lactate (3-fold more) under hypoxia (1% O
2) than under 20% O
2 and (ii) lactate recruits hMSCs towards tumor cells by activating signaling pathways to enhance migration. The mRNA and protein expression of functional MCT1 in hMSCs is increased in response to lactate exposure. Thus, we hypothesized that hMSCs and stromal carcinoma associated fibroblasts (CAFs) in the tumor microenvironment have the capacity to take up lactate expelled from tumor cells and use it as a source of energy. Our
13C NMR spectroscopic measurements indicate that
13C-lactate is converted to
13C-alpha ketoglutarate in hMSCs and CAFs supporting this hypothesis. To our knowledge this is the first
in vitro model system demonstrating that hMSCs and CAFs can utilize lactate produced by tumor cells.
Immunotherapy for pediatric tumors is rapidly evolving. From major successes in pediatric hematologic malignancies, immunotherapy utility increased in the pediatric solid tumor landscape. Numerous ...pediatric solid tumors are defined as rare with limitations in diagnosis and treatment. This review will describe four major immunotherapies used in pediatrics and discuss results seen in rare pediatric tumors. We will also briefly review the challenges of immunotherapy in solid tumors and opportunities to drive this therapy forward.
Despite rare success employing immunotherapy for pediatric solid tumors, recently there have been several successes in pediatric rare solid tumors. After describing the evolving landscape of rare pediatric tumors, we will demonstrate the successes or disappointments of immunotherapy. We will describe the mechanism of four immunotherapies used in the pediatrics, followed by the published results. Finally, we will discuss the challenges and opportunities for immunotherapies in pediatric rare tumors.
Pediatric rare tumors are lacking in treatment options. Despite numerous disappointments utilizing immunotherapies in the more common pediatric solid tumors, there have been several successes within the pediatric rare tumor landscape. Much work is still needed to enhance our understanding and knowledge on utilizing these immunotherapies for pediatric rare solid tumors.
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