Hot off the presses! Sep 08 Cancer Cell

The Sep 08 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:

• The Yin-Yang of Tumor-Associated Neutrophils
  - Cancer Cell 16(3):173-174 (2009)
  Cancer-related inflammation is a key component of the tumor microenvironment. A report in this issue of Cancer Cell now indicates that tumor-associated neutrophils in lung cancer can polarize to either "N1" or "N2" phenotype that inhibits or promotes cancer development, respectively.
• Imatinib Resistance and Progression of CML to Blast Crisis: Somatic Hypermutation AIDing the Way
  - Cancer Cell 16(3):174-176 (2009)
  Very little is known about how acquired oncogenic mutations arise. In this issue of Cancer Cell, Klemm and colleagues present evidence supporting a role for the antibody diversification enzyme activation-induced deaminase (AID) in the generation of mutations associated with disease progression and drug resistance in chronic myeloid leukemia.
• Src Substrate Surprise
  - Cancer Cell 16(3):176-178 (2009)
  In this issue of Cancer Cell, Lowy and colleagues show that the SH2 domain of tensin-3 is regulated by phosphorylation by Src and that this phosphorylation promotes the oncogenic function of tensin-3. Phosphorylation of the SH2 domain represents a novel mechanism for the regulation of SH2 ligand binding.
• A Molecular Link between AKT Regulation and Chemotherapeutic Response
  - Cancer Cell 16(3):178-180 (2009)
  The protein kinase AKT is frequently activated in human cancers and has been implicated in resistance to chemotherapy. In this issue of Cancer Cell, Pei et al. show that FKBP51 negatively regulates AKT through the phosphatase PHLPP. This regulation appears to be a determinant of chemosensitivity in cancer cells.
• SDH5 Mutations and Familial Paraganglioma: Somewhere Warburg is Smiling
  - Cancer Cell 16(3):180-182 (2009)
  Paragangliomas have been linked to mutations affecting the succinate dehydrogenase complex. In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function. Moreover, they detected SDH5 mutations in a large kindred with familial paraganglioma.
• Polarization of Tumor-Associated Neutrophil Phenotype by TGF-β: "N1" versus "N2" TAN
  - Cancer Cell 16(3):183-194 (2009)
  TGF-β blockade significantly slows tumor growth through many mechanisms, including activation of CD8+ T cells and macrophages. Here, we show that TGF-β blockade also increases neutrophil-attracting chemokines, resulting in an influx of CD11b+/Ly6G+ tumor-associated neutrophils (TANs) that are hypersegmented, more cytotoxic to tumor cells, and express higher levels of proinflammatory cytokines. Accordingly, following TGF-β blockade, depletion of these neutrophils significantly blunts antitumor effects of treatment and reduces CD8+ T cell activation. In contrast, in control tumors, neutrophil depletion decreases tumor growth and results in more activated CD8+ T cells intratumorally. Together, these data suggest that TGF-β within the tumor microenvironment induces a population of TAN with a protumor phenotype. TGF-β blockade results in the recruitment and activation of TANs with an antitumor phenotype.
• 14-3-3ζ Cooperates with ErbB2 to Promote Ductal Carcinoma In Situ Progression to Invasive Breast Cancer by Inducing Epithelial-Mesenchymal Transition
  - Cancer Cell 16(3):195-207 (2009)
  ErbB2, a metastasis-promoting oncoprotein, is overexpressed in 25% of invasive/metastatic breast cancers, but in 50%–60% of noninvasive ductal carcinomas in situ (DCIS). It has been puzzling how a subset of ErbB2-overexpressing DCIS develops into invasive breast cancer (IBC). We found that co-overexpression of 14-3-3ζ in ErbB2-overexpressing DCIS conferred a higher risk of progression to IBC. ErbB2 and 14-3-3ζ overexpression, respectively, increased cell migration and decreased cell adhesion, two prerequisites of tumor cell invasion. 14-3-3ζ overexpression reduced cell adhesion by activating the TGF-β/Smads pathway that led to ZFHX1B/SIP-1 upregulation, E-cadherin loss, and epithelial-mesenchymal transition. Importantly, patients whose breast tumors overexpressed both ErbB2 and 14-3-3ζ had higher rates of metastatic recurrence and death than those whose tumors overexpressed only one.
• Colitis-Associated Colorectal Cancer Driven by T-bet Deficiency in Dendritic Cells
  - Cancer Cell 16(3):208-219 (2009)
  We previously described a mouse model of ulcerative colitis linked to T-bet deficiency in the innate immune system. Here, we report that the majority of T-bet−/−RAG2−/− ulcerative colitis (TRUC) mice spontaneously progress to colonic dysplasia and rectal adenocarcinoma solely as a consequence of MyD88-independent intestinal inflammation. Dendritic cells (DCs) are necessary cellular effectors for a proinflammatory program that is carcinogenic. Whereas these malignancies arise in the setting of a complex inflammatory environment, restoration of T-bet selectively in DCs was sufficient to reduce colonic inflammation and prevent the development of neoplasia. TRUC colitis-associated colorectal cancer resembles the human disease and provides ample opportunity to probe how inflammation drives colorectal cancer development and to test preventative and therapeutic strategies preclinically.
• Growth Factor-Antagonized Rexinoid Apoptosis Involves Permissive PPARγ/RXR Heterodimers to Activate the Intrinsic Death Pathway by NO
  - Cancer Cell 16(3):220-231 (2009)
  Growth factor (GF) deprivation and/or blocking of cognate signaling can induce apoptosis and is the basis of several cancer treatment paradigms. We observed that RXR agonists (rexinoids) induce apoptosis of tumor cells when GF support is abrogated. This "rexinoid apoptosis" involves activation of both iNOS and eNOS by RXR-PPARγ and results in production of apoptogenic NO. IGF/EGF-induced IGF receptor 1-mediated MAP kinase blocks rexinoid apoptosis by RXR phosphorylation. Combining rexinoids with the MAPK inhibitor U0126 induced apoptosis in human cancer cells in vitro and ex vivo and blocked xenograft growth in vivo. Our results suggest a regulatory mechanism in which GF signaling antagonizes RXR-PPARγ-mediated default apoptosis to sustain cell life.
• The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug Resistance in Chronic Myeloid Leukemia
  - Cancer Cell 16(3):232-245 (2009)
  Chronic myeloid leukemia (CML) is induced by BCR-ABL1 and can be effectively treated for many years with Imatinib until leukemia cells acquire drug resistance through BCR-ABL1 mutations and progress into fatal B lymphoid blast crisis (LBC). Despite its clinical significance, the mechanism of progression into LBC is unknown. Here, we show that LBC but not CML cells express the B cell-specific mutator enzyme AID. We demonstrate that AID expression in CML cells promotes overall genetic instability by hypermutation of tumor suppressor and DNA repair genes. Importantly, our data uncover a causative role of AID activity in the acquisition of BCR-ABL1 mutations leading to Imatinib resistance, thus providing a rationale for the rapid development of drug resistance and blast crisis progression.
• The Tensin-3 Protein, Including its SH2 Domain, Is Phosphorylated by Src and Contributes to Tumorigenesis and Metastasis
  - Cancer Cell 16(3):246-258 (2009)
  In cell lines from advanced lung cancer, breast cancer, and melanoma, endogenous tensin-3 contributes to cell migration, anchorage-independent growth, and tumorigenesis. Although SH2 domains have not been reported previously to be phosphorylated, the tensin-3 SH2 domain is a physiologic substrate for Src. Tyrosines in the SH2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. In a mouse breast cancer model, tensin-3 tyrosines are phosphorylated in a Src-associated manner in primary tumors, and experimental metastases induced by tumor-derived cell lines depend on endogenous tensin-3. Thus, tensin-3 is implicated as an oncoprotein regulated by Src and possessing an SH2 domain with a previously undescribed mechanism for the regulation of ligand binding.
• FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt
  - Cancer Cell 16(3):259-266 (2009)
  Akt is a central regulator of cell growth. Its activity can be negatively regulated by the phosphatase PHLPP that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1). However, how PHLPP is targeted to Akt is not clear. Here we show that FKBP51 (FK506-binding protein 51) acts as a scaffolding protein for Akt and PHLPP and promotes dephosphorylation of Akt. Furthermore, FKBP51 is downregulated in pancreatic cancer tissue samples and several cancer cell lines. Decreased FKBP51 expression in cancer cells results in hyperphosphorylation of Akt and decreased cell death following genotoxic stress. Overall, our findings identify FKBP51 as a negative regulator of the Akt pathway, with potentially important implications for cancer etiology and response to chemotherapy.
• Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of Medulloblastoma
  - Cancer Cell 16(3):267 (2009)