The following articles are now available at Cancer Cell:
Immediate Early Publications from Cancer Cell: January 6, 2011
HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization and Vessel Normalization through Downregulation of PlGFCharlotte Rolny, Massimiliano Mazzone, Sònia Tugues, Damya Laoui, Irja Johansson, Cathy Coulon, Mario Leonardo Squadrito, Inmaculada Segura, Xiujuan Li, Ellen Knevels, Sandra Costa, Stefan Vinckier, Tom Dresselaer, Peter Åkerud, Maria De Mol, Henriikka Salomäki, Mia Phillipson, Sabine Wyns, Erik Larsson, Ian Buysschaert, Johan Botling, Uwe Himmelreich, Jo A. Van Ginderachter, Michele De Palma, Mieke Dewerchin, Lena Claesson-Welsh, and Peter Carmeliet
Polarization of tumor-associated macrophages (TAMs) to a pro-angiogenic / immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. The authors report here 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 the anti-tumor immune response 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 anti-cancer and anti-angiogenic treatment.
Oncogenic BRAF Induces Melanoma Cell Invasion by Downregulating the cGMP-Specific Phosphodiesterase PDE5A
Imanol Arozarena, Berta Sanchez-Laorden, Leisl Packer, Cristina Hidalgo-Carcedo, Robert Hayward, Amaya Viros, Erik Sahai, and Richard Marais
The authors show here that in melanoma cells oncogenic BRAF, acting through MEK and the transcription factor BRN2, down-regulates the cGMP specific phosphodiesterase PDE5A. Although PDE5A down-regulation causes a small decrease in proliferation, its major impact is to stimulate a dramatic increase in melanoma cell invasion. This is because PDE5A down-regulation leads to an increase in cGMP, which induces an increase in cytosolic Ca++, stimulating increased contractility and inducing invasion. In vivo, this leads to an increase in short-term and long-term colonization of the lungs by these cells. This pathway was not observed in NRAS mutant melanoma or BRAF mutant colorectal cells. Together these data demonstrate that in melanoma cells oncogenic BRAF induces invasion through down regulation of PDE5A.
AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity
Sarat Chandarlapaty, Ayana Sawai, Maurizio Scaltriti, Vanessa Rodrik-Outmezguine, Olivera Grbovic-Huezo, Violeta Serra, Pradip K. Majumder, Jose Baselga, and Neal Rosen
Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. The authors 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, the authors find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.
EZH2 Promotes Expansion of Breast Tumor Initiating Cells through Activation of RAF1-ß-Catenin Signaling
Chun-Ju Chang, Jer-Yen Yang, Weiya Xia, Chun-Te Chen, Xiaoming Xie, Chi-Hong Chao, Wendy A. Woodward, Jung-Mao Hsu, Gabriel N. Hortobagyi, and Mien-Chie Hung
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, the authors 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-ß-catenin signaling to promote BTIC expansion. The authors further reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, could prevent breast cancer progression by eliminating BTICs.
Basal Cell Carcinomas Arise from Hair Follicle Stem Cells in Ptch1+/- Mice
Grace Ying Wang, Joy Wang, Maria-Laura Mancianti, and Ervin H. Epstein
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, the authors 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.
