Hot off the presses! Jan 18 Cancer Cell

The Jan 18 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Polarization of Tumor-Associated Macrophages: A Novel Strategy for Vascular Normalization and Antitumor Immunity
  - Cancer Cells 19(1):1-2 (2011)
  Vascular normalization is an emerging concept in cancer treatment. In this issue of Cancer Cell, Rolny et al. show that histidine-rich glycoprotein normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis. Placental Growth Factor deletion in macrophages phenocopies many of these effects.
• Hard Times for Oncogenic BRAF-Expressing Melanoma Cells
  - Cancer Cells 19(1):3-4 (2011)
  In this issue of Cancer Cell, Arozarena et al. describe that the oncogenic BRAF Val600Glu mutant, which occurs in about half of melanomas, downregulates the cGMP-hydrolysing phosphodiesterase PDE5A in melanoma cells through the ERK-MAPK cascade coupled to the POU-domain transcription factor BRN2, thereby increasing intracellular cGMP levels and promoting invasiveness.
• Keratin 15-Positive Stem Cells Give Rise to Basal Cell Carcinomas in Irradiated Ptch1+/− Mice
  - Cancer Cells 19(1):5-6 (2011)
  The cell of origin for basal cell carcinoma (BCC) remains controversial. In this issue of Cancer Cell, Wang et al. provide strong evidence that BCC arise from hair follicle stem cells.
• Metastatic Colon Cancer Cells Negotiate the Intravasation Notch
  - Cancer Cells 19(1):6-8 (2011)
  In this issue of Cancer Cell, Sonoshita et al. report that Aes/Grg5 prevents metastasis of colorectal cancer cells by sequestering and inactivating Notch transcriptional effectors in distinct nuclear foci. Loss of Aes/Grg5 in invasive cancer cells where Notch is activated by stroma-expressed ligands promotes invasion, transendothelial migration, intravasation, and metastasis.
• Human Acute Myelogenous Leukemia Stem Cells Revisited: There's More Than Meets the Eye
  - Cancer Cells 19(1):9-10 (2011)
  In this issue of Cancer Cell, Goardon et al. revise earlier conclusions regarding acute myelogenous leukemia (AML) stem cells by demonstrating that in the majority of patients, they reside in two hierarchically related populations most similar to normal hematopoietic progenitors. These findings have implications for therapeutic targeting of these cells.
• Mutant BRAF Melanomas—Dependence and Resistance
  - Cancer Cells 19(1):11-15 (2011)
  RAF inhibitors have the unique property of transactivating RAS-dependent RAF dimers in most cells but inhibit RAF/MEK/ERK signaling in cells expressing mutant BRAF, in which RAS activity is too low to support this process. These drugs thus selectively inhibit ERK signaling in tumors with BRAF mutation. RAF inhibitors have remarkable clinical activity in melanomas with BRAFV600E mutations; however, resistance invariably develops. Three recent papers reveal that acquired resistance may be due to mechanisms that cause ERK signaling to become insensitive to RAF inhibitors, or that reduce the dependence of the tumor on ERK signaling through activation of other pathways.
• Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases
  - Cancer Cells 19(1):17-30 (2011)
  IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.
• HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization and Vessel Normalization through Downregulation of PlGF
  - Cancer Cells 19(1):31-44 (2011)
  Polarization of tumor-associated macrophages (TAMs) to a proangiogenic/immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. We report that the host-produced histidine-rich glycoprotein (HRG) inhibits tumor growth and metastasis, while improving chemotherapy. By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HRG relies substantially on downregulation of placental growth factor (PlGF). Besides unveiling an important role for TAM polarization in tumor vessel abnormalization, and its regulation by HRG/PlGF, these findings offer therapeutic opportunities for anticancer and antiangiogenic treatment.
• Oncogenic BRAF Induces Melanoma Cell Invasion by Downregulating the cGMP-Specific Phosphodiesterase PDE5A
  - Cancer Cells 19(1):45-57 (2011)
  We show that in melanoma cells oncogenic BRAF, acting through MEK and the transcription factor BRN2, downregulates the cGMP-specific phosphodiesterase PDE5A. Although PDE5A downregulation causes a small decrease in proliferation, its major impact is to stimulate a dramatic increase in melanoma cell invasion. This is because PDE5A downregulation leads to an increase in cGMP, which induces an increase in cytosolic Ca2+, stimulating increased contractility and inducing invasion. PDE5A downregulation also this leads to an increase in short-term and long-term colonization of the lungs by melanoma cells. We do not observe this pathway in NRAS mutant melanoma or BRAF mutant colorectal cells. Thus, we show that in melanoma cells oncogenic BRAF induces invasion through downregulation of PDE5A.
• AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity
  - Cancer Cells 19(1):58-71 (2011)
  Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.
• Endogenous T Cell Responses to Antigens Expressed in Lung Adenocarcinomas Delay Malignant Tumor Progression
  - Cancer Cells 19(1):72-85 (2011)
  Neoantigens derived from somatic mutations in tumors may provide a critical link between the adaptive immune system and cancer. Here, we describe a system to introduce exogenous antigens into genetically engineered mouse lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors.
• EZH2 Promotes Expansion of Breast Tumor Initiating Cells through Activation of RAF1-β-Catenin Signaling
  - Cancer Cells 19(1):86-100 (2011)
  It has been proposed that an aggressive secondary cancer stem cell population arises from a primary cancer stem cell population through acquisition of additional genetic mutations and drives cancer progression. Overexpression of Polycomb protein EZH2, essential in stem cell self-renewal, has been linked to breast cancer progression. However, critical mechanism linking increased EZH2 expression to BTIC (breast tumor initiating cell) regulation and cancer progression remains unclear. Here, we identify a mechanism in which EZH2 expression-mediated downregulation of DNA damage repair leads to accumulation of recurrent RAF1 gene amplification in BTICs, which activates p-ERK-β-catenin signaling to promote BTIC expansion. We further reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, could prevent breast cancer progression by eliminating BTICs.
• An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells
  - Cancer Cells 19(1):101-113 (2011)
  Antibodies to cell-surface antigens trigger activatory Fcγ receptor (FcγR)-mediated retrograde signals in leukocytes to control immune effector functions. Here, we uncover an FcγR mechanism that drives antibody-dependent forward signaling in target cells. Agonistic antibodies to death receptor 5 (DR5) induce cancer-cell apoptosis and are in clinical trials; however, their mechanism of action in vivo is not fully defined. Interaction of the DR5-agonistic antibody drozitumab with leukocyte FcγRs promoted DR5-mediated tumor-cell apoptosis. Whereas the anti-CD20 antibody rituximab required activatory FcγRs for tumoricidal function, drozitumab was effective in the context of either activatory or inhibitory FcγRs. A CD40-agonistic antibody required similar FcγR interactions to stimulate nuclear factor-κB activity in B cells. Thus, FcγRs can drive antibody-mediated receptor signaling in target cells.
• Basal Cell Carcinomas Arise from Hair Follicle Stem Cells in Ptch1+/− Mice
  - Cancer Cells 19(1):114-124 (2011)
  Basal cell carcinomas (BCCs) are hedgehog-driven tumors that resemble follicular and interfollicular epidermal basal keratinocytes and hence long have been thought to arise from these cells. However, the actual cell of origin is unknown. Using cell fate tracking of X-ray induced BCCs in Ptch1+/− mice, we found their essentially exclusive origin to be keratin 15-expressing stem cells of the follicular bulge. However, conditional loss of p53 not only enhanced BCC carcinogenesis from the bulge but also produced BCCs from the interfollicular epidermis, at least in part by enhancing Smo expression. This latter finding is consistent with the lack of visible tumors on ears and tail, sites lacking Smo expression, in Ptch1+/− mice.
• Suppression of Colon Cancer Metastasis by Aes through Inhibition of Notch Signaling
  - Cancer Cells 19(1):125-137 (2011)
  Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in ApcΔ716 intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.
• Coexistence of LMPP-like and GMP-like Leukemia Stem Cells in Acute Myeloid Leukemia
  - Cancer Cells 19(1):138-152 (2011)
  The relationships between normal and leukemic stem/progenitor cells are unclear. We show that in 80% of primary human CD34+ acute myeloid leukemia (AML), two expanded populations with hemopoietic progenitor immunophenotype coexist in most patients. Both populations have leukemic stem cell (LSC) activity and are hierarchically ordered; one LSC population gives rise to the other. Global gene expression profiling shows the LSC populations are molecularly distinct and resemble normal progenitors but not stem cells. The more mature LSC population most closely mirrors normal granulocyte-macrophage progenitors (GMP) and the immature LSC population a previously uncharacterized progenitor functionally similar to lymphoid-primed multipotential progenitors (LMPPs). This suggests that in most cases primary CD34+ AML is a progenitor disease where LSCs acquire abnormal self-renewal potential.
• Epigenetic Antagonism between Polycomb and SWI/SNF Complexes during Oncogenic Transformation
  - Cancer Cells 19(1):153 (2011)
  
• Overexpression of Interleukin-1β Induces Gastric Inflammation and Cancer and Mobilizes Myeloid-Derived Suppressor Cells in Mice
  - Cancer Cells 19(1):154 (2011)