The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.

Activin-A is a transforming growth factor-␤ (TGF-␤) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immuneregulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs IntroductionDendritic cells (DCs) form sentinel networks within the body sampling the microenvironment for pathogens, tissue injury, and inflammation via an array of pattern recognition receptors. [1][2][3] Pathogen encounter induces DC maturation, resulting in profound alterations in DC function. Antigen uptake is reduced, antigen processing is enhanced, and proinflammatory mediators are released. [4][5][6][7][8] The class, magnitude, and timing of cytokine or chemokine release are under exquisite control through both autocrine and paracrine signals as well as the signal strength and magnitude of the initiating stimulus. 8 DC cytokine and chemokine production can be induced by specific classes of stimuli. These include CD40 ligand (CD40L) and pathogen signals, such as toll-like receptor (TLR) agonists (eg, lipopolysaccharide [LPS] or intact bacteria). Appropriate release of cytokines, chemokines, and other soluble mediators by DCs and neighboring cells induces and moderates inflammation, recruits innate effectors, and regulates T-cell functions. [9][10][11][12] Many cytokines/chemokines produced by DCs at the epicenter of infection and inflammation, such as interleukin-6 (IL-6), 13,14 IL-8, 4,15,16 IL-10 17,18 as well as the potent T helper 1 (Th-1) cytokine, 19,20 have pleiotropic effects ranging from enhancing to inhibitory depending on the context and target cell type. However, uncontrolled cytokine/chemokine release within this microenvironment can also result in inappropriate T-and B-cell responses and subsequent immunopathology. [21][22][23] In this regard, the immune system has evolved to coordinately express mediators that attenuate exaggerated or inappropriate responses so as to minimize tissue damage and immunopathology (eg, prostaglandin E 2 (PGE 2 ), adenosine triphosphate (ATP), transforming growth factor-␤ [TGF-␤]). 24 Activin-A is a homodimer of activin-␤A subunits and was first described as a reproductive factor that accentuates the release of follicle-stimulating hormone. 25 It is a member of the TGF-␤ superfamily of cytokines and intimately shares with TGF-␤ the Smad intracellular signaling proteins. 26 The signaling, however, occurs through separate and distinct serine threonine kinase receptor subunits, and its release into the circulation during acute systemic inflammation differs from TGF-␤. 27 Activin-A signals through heteromeric receptor complexes consisting of both type I (ALK 2, 4, or 7) and type II (ActRIIA and ActRIIB) receptors. In addition, it is known to be pivotal in ...

A common mutation of the epidermal growth factor receptor (EGFR) in glioblastoma multiforme (GBM) is an extracellular truncation known as the de2-7 EGFR (or EGFRvIII). Hepatocyte growth factor (HGF) is the ligand for the receptor tyrosine kinase (RTK) c-Met, and this signaling axis is often active in GBM. The expression of the HGF/c-Met axis or de2-7 EGFR independently enhances GBM growth and invasiveness, particularly through the phosphatidylinositol-3 kinase/pAkt pathway. Using RTK arrays, we show that expression of de2-7 EGFR in U87MG GBM cells leads to the coactivation of several RTKs, including platelet-derived growth factor receptor beta and c-Met. A neutralizing antibody to HGF (AMG102) did not inhibit de2-7 EGFR-mediated activation of c-Met, demonstrating that it is ligand-independent. Therapy for parental U87MG xenografts with AMG 102 resulted in significant inhibition of tumor growth, whereas U87MG.Delta 2-7 xenografts were profoundly resistant. Treatment of U87MG.Delta 2-7 xenografts with panitumumab, an anti-EGFR antibody, only partially inhibited tumor growth as xenografts rapidly reverted to the HGF/c-Met signaling pathway. Cotreatment with panitumumab and AMG 102 prevented this escape leading to significant tumor inhibition through an apoptotic mechanism, consistent with the induction of oncogenic shock. This observation provides a rationale for using panitumumab and AMG 102 in combination for the treatment of GBM patients. These results illustrate that GBM cells can rapidly change the RTK driving their oncogene addiction if the alternate RTK signals through the same downstream pathway. Consequently, inhibition of a dominant oncogene by targeted therapy can alter the hierarchy of RTKs resulting in rapid therapeutic resistance.

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