Activation of Cre Recombinase Alone Can Induce Complete Tumor Regression
2014; 9 (9)
MYC through miR-17-92 Suppresses Specific Target Genes to Maintain Survival, Autonomous Proliferation, and a Neoplastic State.
2014; 26 (2): 262-272
Inactivation of MYC reverses tumorigenesis
JOURNAL OF INTERNAL MEDICINE
2014; 276 (1): 52-60
The MYC oncogene regulates gene expression through multiple mechanisms, and its overexpression culminates in tumorigenesis. MYC inactivation reverses turmorigenesis through the loss of distinguishing features of cancer, including autonomous proliferation and survival. Here we report that MYC via miR-17-92 maintains a neoplastic state through the suppression of chromatin regulatory genes Sin3b, Hbp1, Suv420h1, and Btg1, as well as the apoptosis regulator Bim. The enforced expression of miR-17-92 prevents MYC suppression from inducing proliferative arrest, senescence, and apoptosis and abrogates sustained tumor regression. Knockdown of the five miR-17-92 target genes blocks senescence and apoptosis while it modestly delays proliferative arrest, thus partially recapitulating miR-17-92 function. We conclude that MYC, via miR-17-92, maintains a neoplastic state by suppressing specific target genes.
View details for DOI 10.1016/j.ccr.2014.06.014
View details for PubMedID 25117713
An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation
2014; 58 (2-3): 282-291
The MYC proto-oncogene is an essential regulator of many normal biological programmes. MYC, when activated as an oncogene, has been implicated in the pathogenesis of most types of human cancers. MYC overexpression in normal cells is restrained from causing cancer through multiple genetically and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis and cellular senescence. When pathologically activated in the correct epigenetic and genetic contexts, MYC bypasses these mechanisms and drives many of the 'hallmark' features of cancer, including uncontrolled tumour growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis and altered cellular metabolism. MYC also dictates tumour cell fate by enforcing self-renewal and by abrogating cellular senescence and differentiation programmes. Moreover, MYC influences the tumour microenvironment, including activating angiogenesis and suppressing the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can lead to the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumour regression associated with tumour cells undergoing proliferative arrest, differentiation, senescence and apoptosis, as well as remodelling of the tumour microenvironment, recruitment of an immune response and shutdown of angiogenesis. Hence, tumours appear to be addicted to the MYC oncogene because of both tumour cell intrinsic and host-dependent mechanisms. MYC is important for the regulation of both the initiation and maintenance of tumorigenesis. This article is protected by copyright. All rights reserved.
View details for DOI 10.1111/joim.12237
View details for Web of Science ID 000337787500006
Angiocrine Factors Deployed by Tumor Vascular Niche Induce B Cell Lymphoma Invasiveness and Chemoresistance
2014; 25 (3): 350-365
Tumors are genetically complex and can have a multitude of mutations. Consequently, it is surprising that the suppression of a single oncogene can result in rapid and sustained tumor regression, illustrating the concept that cancers are often "oncogene addicted." The mechanism of oncogene addiction has been presumed to be largely cell autonomous as a consequence of the restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and/or cellular senescence. Interestingly, it has recently become apparent that upon oncogene inactivation, the immune response is critical in mediating the phenotypic consequences of oncogene addiction. In particular, CD4(+) T cells have been suggested to be essential to the remodeling of the tumor microenvironment, including the shutdown of host angiogenesis and the induction of cellular senescence in the tumor. However, adaptive and innate immune cells are likely involved. Thus, the effectors of the immune system are involved not only in tumor initiation, tumor progression, and immunosurveillance, but also in the mechanism of tumor regression upon targeted oncogene inactivation. Hence, oncogene inactivation may be an effective therapeutic approach because it both reverses the neoplastic state within a cancer cell and reactivates the host immune response that remodels the tumor microenvironment.
View details for DOI 10.1007/s12026-014-8503-6
View details for Web of Science ID 000336333700015
View details for PubMedID 24791942
Oncogene withdrawal engages the immune system to induce sustained cancer regression.
Journal for immunotherapy of cancer
2014; 2: 24-?
Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.
View details for DOI 10.1016/j.ccr.2014.02.005
View details for Web of Science ID 000333233400012
Therapeutic targeting of BRCA1-mutated breast cancers with agents that activate DNA repair.
The targeted inactivation of a single oncogene can induce dramatic tumor regression, suggesting that cancers are "oncogene addicted." Tumor regression following oncogene inactivation has been thought to be a consequence of restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and cellular senescence. However, recent observations illustrate that oncogene addiction is highly dependent upon the host immune cells. In particular, CD4(+) helper T cells were shown to be essential to the mechanism by which MYC or BCR-ABL inactivation elicits "oncogene withdrawal." Hence, immune mediators contribute in multiple ways to the pathogenesis, prevention, and treatment of cancer, including mechanisms of tumor initiation, progression, and surveillance, but also oncogene inactivation-mediated tumor regression. Data from both the bench and the bedside illustrates that the inactivation of a driver oncogene can induce activation of the immune system that appears to be essential for sustained tumor regression.
View details for DOI 10.1186/2051-1426-2-24
View details for PubMedID 25089198
Noncanonical roles of the immune system in eliciting oncogene addiction
CURRENT OPINION IN IMMUNOLOGY
2013; 25 (2): 246-258
Cancers due to germline mutations in the BRCA1 gene tend to lack targets for approved chemoprevention agents. This study aimed at a targeted chemoprevention strategy for BRCA1-associated malignancies. Mutant BRCA1 limits the base-excision DNA repair activity that addresses oxidative DNA damage, the accumulation of which heightens one's risk for cancer. Therefore, we conducted a high-throughput chemical screen to identify drug candidates that could attenuate the inhibitory effects of mutant BRCA1 on this repair activity, thereby describing a new class of DNA repair-activating chemopreventive agents. In the screen design, such drugs functioned by enhancing base-excision DNA repair of oxidative DNA damage in the presence of mutant BRCA1, with minimal cytotoxicity. We identified at least one new agent that decreased malignant properties associated with tumorigenesis, including anchorage-independent growth and tumor progression. This work offers a preclinical proof-of-concept for a wholly new approach to chemoprevention in carriers of BRCA1 mutations, as a strategy to reduce the prevalence of BRCA1-associated malignancy.
View details for DOI 10.1158/0008-5472.CAN-14-1716
View details for PubMedID 25217519
Science and policy on endocrine disrupters must not be mixed: a reply to a "common sense" intervention by toxicology journal editors.
2013; 12(1):69.: Aug 27;12(1):69.
Bisphenol A Diglycidyl Ether Induces Adipogenic Differentiation of Multipotent Stromal Stem Cells through a Peroxisome Proliferator-Activated Receptor Gamma-Independent Mechanism
ENVIRONMENTAL HEALTH PERSPECTIVES
2012; 120 (7): 984-989
Cancer is highly complex. The magnitude of this complexity makes it highly surprising that even the brief suppression of an oncogene can sometimes result in rapid and sustained tumor regression, illustrating that cancers can be 'oncogene addicted' [1-10]. The essential implication is that oncogenes may not only fuel the initiation of tumorigenesis, but in some cases must be excessively activated to maintain a neoplastic state . Oncogene suppression acutely restores normal physiological programs that effectively overrides secondary genetic events and a cancer collapses [12,13]. Oncogene addiction is the description of the dramatic and sustained regression of some cancers upon the specific inactivation of a single oncogene [1-13,14(••),15,16(••)], that can occur through tumor intrinsic [1,2,4,12], but also host immune mechanisms [17-23]. Notably, oncogene inactivation elicits a host immune response that involves specific immune effectors and cytokines that facilitate a remodeling of the tumor microenvironment including the shut down of angiogenesis and the induction of cellular senescence of tumor cells [16(••)]. Hence, immune effectors are not only critically involved in tumor prevention, initiation [17-19], and progression , but also appear to be essential to tumor regression upon oncogene inactivation [21,22(••),23(••)]. Understanding how the inactivation of an oncogene elicits a systemic signal in the host that prompts a deconstruction of a tumor could have important implications. The combination of oncogene-targeted therapy together with immunomodulatory therapy may be ideal for the development of both robust tumor intrinsic and immunological responses, effectively leading to sustained tumor regression.
View details for DOI 10.1016/j.coi.2013.02.003
View details for Web of Science ID 000319369100018
The Steroid and Xenobiotic Receptor Negatively Regulates B-1 Cell Development in the Fetal Liver
2012; 26 (6): 916-925
Bisphenol A (BPA) and bisphenol A diglycidyl ether (BADGE), used in manufacturing coatings and resins, leach from packaging materials into food. Numerous studies suggested that BPA and BADGE may have adverse effects on human health, including the possibility that exposure to such chemicals can be superimposed on traditional risk factors to initiate or exacerbate the development of obesity. BPA is a suspected obesogen, whereas BADGE, described as a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, could reduce weight gain.We sought to test the adipogenic effects of BADGE in a biologically relevant cell culture model.We used multipotent mesenchymal stromal stem cells (MSCs) to study the adipogenic capacity of BADGE and BPA and evaluated their effects on adipogenesis, osteogenesis, gene expression, and nuclear receptor activation.BADGE induced adipogenesis in human and mouse MSCs, as well as in mouse 3T3-L1 preadipocytes. In contrast, BPA failed to promote adipogenesis in MSCs, but induced adipogenesis in 3T3-L1 cells. BADGE exposure elicited an adipogenic gene expression profile, and its ability to induce adipogenesis and the expression of adipogenic genes was not blocked by known PPARγ antagonists. Neither BADGE nor BPA activated or antagonized retinoid "X" receptor (RXR) or PPARγ in transient transfection assays.BADGE can induce adipogenic differentiation in both MSCs and in preadipocytes at low nanomolar concentrations comparable to those that have been observed in limited human biomonitoring. BADGE probably acts through a mechanism that is downstream of, or parallel to, PPARγ.
View details for DOI 10.1289/ehp.1205063
View details for Web of Science ID 000306035300023
View details for PubMedID 22763116
B-1 Cell Lymphoma in Mice Lacking the Steroid and Xenobiotic Receptor, SXR
2011; 25 (6): 933-943
The steroid and xenobiotic receptor (SXR) (also known as pregnane X receptor or PXR) is a broad-specificity nuclear hormone receptor that is well known for its role in drug and xenobiotic metabolism. SXR is activated by a wide variety of endobiotics, dietary compounds, pharmaceuticals, and xenobiotic chemicals. SXR is expressed at its highest levels in the liver and intestine yet is found in lower levels in other tissues, where its roles are less understood. We previously demonstrated that SXR(-/-) mice demonstrate elevated nuclear factor (NF)-κB activity and overexpression of NF-κB target genes and that SXR(-/-) mice develop lymphoma derived from B-1 lymphocytes in an age-dependent manner. In this work, we show that fetal livers in SXR(-/-) mice display elevated expression of NF-κB target genes and possess a significantly larger percentage of B-1 progenitor cells in the fetal liver. Furthermore, in utero activation of SXR in wild-type mice reduces the B-1 progenitor populations in the embryonic liver and reduces the size of the B-1 cell compartment in adult animals that were treated in utero. This suggests that activation of SXR during development may permanently alter the immune system of animals exposed in utero, demonstrating a novel role for SXR in the generation of B-1 cell precursors in the fetal liver. These data support our previous findings that SXR functions as a tumor suppressor in B-1 lymphocytes and establish a unique role for SXR as a modulator of developmental hematopoiesis in the liver.
View details for DOI 10.1210/me.2011-1303
View details for Web of Science ID 000304365100004
View details for PubMedID 22496360
Pregnane X receptor knockout mice display osteopenia with reduced bone formation and enhanced bone resorption
JOURNAL OF ENDOCRINOLOGY
2010; 207 (3): 257-263
The steroid and xenobiotic receptor (SXR) is a broad-specificity nuclear hormone receptor that is highly expressed in the liver and intestine, where its primary function is to regulate drug and xenobiotic metabolism. SXR is expressed at lower levels in other tissues, where little is known about its physiological functions. We previously linked SXR with immunity and inflammation by showing that SXR antagonizes the activity of nuclear factor (NF)-κB in vitro and in vivo. SXR(-/-) mice demonstrate aberrantly high NF-κB activity and overexpression of NF-κB target genes. Here we show that SXR(-/-) mice develop B cell lymphoma in an age-dependent manner. SXR(-/-) mice develop multiple hyperplastic lymphoid foci composed of B-1a cells in the intestine, spleen, lymph nodes, peritoneal cavity, and blood. In all circumstances, these lymphocytes possess cell surface and molecular characteristics of either chronic lymphocytic leukemia or non-Hodgkin's lymphoma originating from B-1 lymphocytes. These results demonstrate a novel and unsuspected role for SXR signaling in the B-1 cell compartment, establish SXR as a tumor suppressor in B-1 cells, and may provide a link between metabolism of xenobiotic compounds and lymphomagenesis.
View details for DOI 10.1210/me.2010-0486
View details for Web of Science ID 000290791600004
View details for PubMedID 21436254
Prenatal Exposure to the Environmental Obesogen Tributyltin Predisposes Multipotent Stem Cells to Become Adipocytes
2010; 24 (3): 526-539
The steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and intestine where they function as xenobiotic sensors. In addition to its role as a xenobiotic sensor, previous studies in our laboratories and elsewhere have identified a role for SXR/PXR as a mediator of bone homeostasis. Here, we report that systemic deletion of PXR results in marked osteopenia with mechanical fragility in female mice as young as 4 months old. Bone mineral density (BMD) of PXR knockout (PXRKO) mice was significantly decreased compared with the BMD of wild-type (WT) mice. Micro-computed tomography analysis of femoral trabecular bones revealed that the three-dimensional bone volume fraction of PXRKO mice was markedly reduced compared with that of WT mice. Histomorphometrical analysis of the trabecular bones in the proximal tibia showed a remarkable reduction in bone mass in PXRKO mice. As for bone turnover of the trabecular bones, bone formation is reduced, whereas bone resorption is enhanced in PXRKO mice. Histomorphometrical analysis of femoral cortical bones revealed a larger cortical area in WT mice than that in PXRKO mice. WT mice had a thicker cortical width than PXRKO mice. Three-point bending test revealed that these morphological phenotypes actually caused mechanical fragility. Lastly, serum levels of phosphate, calcium, and alkaline phosphatase were unchanged in PXRKO mice compared with WT. Consistent with our previous results, we conclude that SXR/PXR promotes bone formation and suppresses bone resorption thus cementing a role for SXR/PXR as a key regulator of bone homeostasis.
View details for DOI 10.1677/JOE-10-0208
View details for Web of Science ID 000284490300002
View details for PubMedID 20876238
The environmental obesogen hypothesis proposes that pre- and postnatal exposure to environmental chemicals contributes to adipogenesis and the development of obesity. Tributyltin (TBT) is an agonist of both retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPARgamma). Activation of these receptors can elevate adipose mass in adult mice exposed to the chemical in utero. Here we show that TBT sensitizes human and mouse multipotent stromal stem cells derived from white adipose tissue [adipose-derived stromal stem cells (ADSCs)] to undergo adipogenesis. In vitro exposure to TBT, or the PPARgamma activator rosiglitazone increases adipogenesis, cellular lipid content, and expression of adipogenic genes. The adipogenic effects of TBT and rosiglitazone were blocked by the addition of PPARgamma antagonists, suggesting that activation of PPARgamma mediates the effect of both compounds on adipogenesis. ADSCs from mice exposed to TBT in utero showed increased adipogenic capacity and reduced osteogenic capacity with enhanced lipid accumulation in response to adipogenic induction. ADSCs retrieved from animals exposed to TBT in utero showed increased expression of PPARgamma target genes such as the early adipogenic differentiation gene marker fatty acid-binding protein 4 and hypomethylation of the promoter/enhancer region of the fatty acid-binding protein 4 locus. Hence, TBT alters the stem cell compartment by sensitizing multipotent stromal stem cells to differentiate into adipocytes, an effect that could likely increase adipose mass over time.
View details for DOI 10.1210/me.2009-0261
View details for Web of Science ID 000274929600005
View details for PubMedID 20160124