Hot off the presses! Aug 04 Cancer Cell

The Aug 04 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:

• Metastasis-Promoting Immunity: When T Cells Turn to the Dark Side
  Pardoll D - Cancer Cell 16(2):81-82 (2009)
  While the role of endogenous T cells in antitumor immunity is being debated, little is known about whether and how T cells promote tumorigenesis. In this issue of Cancer Cell, DeNardo and colleagues demonstrate that IL-4-producing T cells enhance metastasis by programming macrophages to produce factors that enhance tumor invasion.
• Tricking Melanoma to Self-Digest: A Deal of a Meal!
  Kim H Ronai Z - Cancer Cell 16(2):83-84 (2009)
  Melanoma cells acquire multiple genetic and epigenetic alterations that promote their metastasis and resistance to available therapies. In this issue of Cancer Cell, Soengas and colleagues reveal that the induction of endosome-mediated autophagy results in efficient melanoma cell death, thereby offering new potential means for treatment of this devastating cancer.
• Raf-1 and Squamous Cell Carcinoma: Rok-ing the Boat
  Grabocka E Bar-Sagi D - Cancer Cell 16(2):85-86 (2009)
  Squamous cell carcinoma (SCC) is the second most common form of nonmelanoma skin cancer. In this issue of Cancer Cell, Ehrenreiter et al. unveil a critical role for the Raf-1/Rok-α interaction in the pathogenesis of SCCs, thus paving the way for the development of therapeutic modalities to treat this malignancy.
• The SPS Affair: A Complex Tale of Illicit Proliferation
  Braun BS Shannon K - Cancer Cell 16(2):87-88 (2009)
  In this issue of Cancer Cell, Xiao et al. report that PLC-β3 mutant mice develop myeloprolfierative neoplasms and show that tumor suppressor activity does not require PLC-β3 catalytic activity. Instead, PLC-β3 forms a complex with SHP-1 and Stat5 that facilitates Stat5 dephosphorylation. A similar mechanism may be operative in some human leukemias.
• Targeting the Molecular Defect in BRCA-Deficient Tumors for Cancer Therapy
  Venkitaraman AR - Cancer Cell 16(2):89-90 (2009)
  Targeted therapies exploiting specific molecular defects in cancer cells promise to overcome roadblocks in the development of effective anticancer drugs. A recent report in the New England Journal of Medicine on the early clinical evaluation of Olaparib in cancers lacking the BRCA1 or BRCA2 genes exemplifies this promising new trend.
• CD4+ T Cells Regulate Pulmonary Metastasis of Mammary Carcinomas by Enhancing Protumor Properties of Macrophages
  Denardo DG Barreto JB Andreu P Vasquez L Tawfik D Kolhatkar N Coussens LM - Cancer Cell 16(2):91-102 (2009)
  During breast cancer development, increased presence of leukocytes in neoplastic stroma parallels disease progression; however, the functional significance of leukocytes in regulating protumor versus antitumor immunity in the breast remains poorly understood. Utilizing the MMTV-PyMT model of mammary carcinogenesis, we demonstrate that IL-4-expressing CD4+ T lymphocytes indirectly promote invasion and subsequent metastasis of mammary adenocarcinomas by directly regulating the phenotype and effector function of tumor-associated CD11b+Gr1-F4/80+ macrophages that in turn enhance metastasis through activation of epidermal growth factor receptor signaling in malignant mammary epithelial cells. Together, these data indicate that antitumor acquired immune programs can be usurped in protumor microenvironments and instead promote malignancy by engaging cellular components of the innate immune system functionally involved in regulating epithelial cell behavior.
• Targeted Activation of Innate Immunity for Therapeutic Induction of Autophagy and Apoptosis in Melanoma Cells
  Tormo D Checińska A Alonso-Curbelo D Pérez-Guijarro E Cañón E Riveiro-Falkenbach E Calvo TG Larribere L Megías D Mulero F Piris MA Dash R Barral PM Rodríguez-Peralto JL Ortiz-Romero P Tüting T Fisher PB Soengas MS - Cancer Cell 16(2):103-114 (2009)
  Inappropriate drug delivery, secondary toxicities, and persistent chemo- and immunoresistance have traditionally compromised treatment response in melanoma. Using cellular systems and genetically engineered mouse models, we show that melanoma cells retain an innate ability to recognize cytosolic double-stranded RNA (dsRNA) and mount persistent stress response programs able to block tumor growth, even in highly immunosuppressed backgrounds. The dsRNA mimic polyinosine-polycytidylic acid, coadministered with polyethyleneimine as carrier, was identified as an unanticipated inducer of autophagy downstream of an exacerbated endosomal maturation program. A concurrent activity of the dsRNA helicase MDA-5 driving the proapoptotic protein NOXA resulted in an efficient autodigestion of melanoma cells. These results reveal tractable links for therapeutic intervention among dsRNA helicases, endo/lysosomes, and apoptotic factors.
• Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K Signaling
  Gewinner C Wang ZC Richardson A Teruya-Feldstein J Etemadmoghadam D Bowtell D Barretina J Lin WM Rameh L Salmena L Pandolfi PP Cantley LC - Cancer Cell 16(2):115-125 (2009)
  We report that knocking down the expression of inositol polyphosphate 4-phosphatase type II (INPP4B) in human epithelial cells, like knockdown of PTEN, resulted in enhanced Akt activation and anchorage-independent growth and enhanced overall motility. In xenograft experiments, overexpression of INPP4B resulted in reduced tumor growth. INPP4B preferentially hydrolyzes phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) with no effect on phosphatidylinositol-3.4.5-triphosphate (PI(3,4,5)P3), suggesting that PI(3,4)P2 and PI(3,4,5)P3 may cooperate in Akt activation and cell transformation. Dual knockdown of INPP4B and PTEN resulted in cellular senescence. Finally, we found loss of heterozygosity (LOH) at the INPP4B locus in a majority of basal-like breast cancers, as well as in a significant fraction of ovarian cancers, which correlated with lower overall patient survival, suggesting that INPP4B is a tumor suppressor.
• Gli2 and p53 Cooperate to Regulate IGFBP-3- Mediated Chondrocyte Apoptosis in the Progression from Benign to Malignant Cartilage Tumors
  Ho L Stojanovski A Whetstone H Wei QX Mau E Wunder JS Alman B - Cancer Cell 16(2):126-136 (2009)
  Clinical evidence suggests that benign cartilage lesions can progress to malignant chondrosarcoma, but the molecular events in this progression are unknown. Mice that develop benign cartilage lesions due to overexpression of Gli2 in chondrocytes developed lesions similar to chondrosarcomas when they were also deficient in p53. Gli2 overexpression and p53 deficiency had opposing effects on chondrocyte differentiation, but had additive effects negatively regulating apoptosis. Regulation of Igfbp3 expression and insulin-like growth factor (IGF) signaling by Gli and p53 integrated their effect on apoptosis. Treatment of human chondrosarcomas or fetal mouse limb explants with IGFBP3 or by blocking IGF increased the apoptosis rate, and mice expressing Gli2 developed substantially fewer tumors when they were also deficient for Igf2. IGF signaling-meditated apoptosis regulates the progression to malignant chondrosarcoma.
• Persistence of Leukemia-Initiating Cells in a Conditional Knockin Model of an Imatinib-Responsive Myeloproliferative Disorder
  Oravecz-Wilson KI Philips ST Yilmaz OH Ames HM Li L Crawford BD Gauvin AM Lucas PC Sitwala K Downing JR Morrison SJ Ross TS - Cancer Cell 16(2):137-148 (2009)
  Despite remarkable responses to the tyrosine kinase inhibitor imatinib, CML patients are rarely cured by this therapy perhaps due to imatinib refractoriness of leukemia-initiating cells (LICs). Evidence for this is limited because of poor engraftment of human CML-LICs in NOD-SCID mice and nonphysiologic expression of oncogenes in retroviral transduction mouse models. To address these challenges, we generated mice bearing conditional knockin alleles of two human oncogenes: HIP1/PDGFβR (H/P) and AML1-ETO (A/E). Unlike retroviral transduction, physiologic expression of H/P or A/E individually failed to induce disease, but coexpression of both H/P and A/E led to rapid onset of a fully penetrant, myeloproliferative disorder, indicating cooperativity between these two alleles. Although imatinib dramatically decreased disease burden, LICs persisted, demonstrating imatinib refractoriness of LICs.
• Raf-1 Addiction in Ras-Induced Skin Carcinogenesis
  Ehrenreiter K Kern F Velamoor V Meissl K Galabova-Kovacs G Sibilia M Baccarini M - Cancer Cell 16(2):149-160 (2009)
  Ras activation is common to many human cancers and promotes cell proliferation and survival by initiating multiple signaling cascades. Accordingly, Ras-transformed cells are generally considered too resourceful to become addicted to a single effector. In contrast to this tenet, we now demonstrate an absolute, cell autonomous requirement for Raf-1 in the development and maintenance of Ras-induced skin epidermis tumors. Mechanistically, Raf-1 functions as an endogenous inhibitor dimming the activity of the Rho-dependent kinase Rok-α in the context of a Ras-induced Raf-1:Rok-α complex. Raf-1-induced Rok-α inhibition allows the phosphorylation of STAT3 and Myc expression and promotes dedifferentiation in Ras-induced tumors. These data link the Raf-1:Rok-α complex to STAT3/Myc activation and delineate a pathway crucial for cell fate decision in Ras-induced tumorigenesis.
• Tumor Suppression by Phospholipase C-β3 via SHP-1-Mediated Dephosphorylation of Stat5
  Xiao W Hong H Kawakami Y Kato Y Wu D Yasudo H Kimura A Kubagawa H Bertoli LF Davis RS Chau LA Madrenas J Hsia CC Xenocostas A Kipps TJ Hennighausen L Iwama A Nakauchi H Kawakami T - Cancer Cell 16(2):161-171 (2009)
  Given its catalytic activity to generate diacylglycerol and inositol 1,4,5-trisphosphate, phospholipase C (PLC) is implicated in promoting cell growth. However, we found that PLC-β3-deficient mice develop myeloproliferative disease, lymphoma, and other tumors. The mutant mice have increased numbers of hematopoietic stem cells with increased proliferative, survival, and myeloid-differentiative abilities. These properties are dependent on Stat5 and can be antagonized by the protein phosphatase SHP-1. Stat5-dependent cooperative transformation by active c-Myc and PLC-β3 deficiency was suggested in mouse lymphomas in PLC-β3−/− and in Eμ-myc;PLC-β3+/− mice and human Burkitt's lymphoma cells. The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-β3 is likely a tumor suppressor.
• Expression of Autotaxin and Lysophosphatidic Acid Receptors Increases Mammary Tumorigenesis, Invasion, and Metastases
  - Cancer Cell 16(2):172 (2009)