Monoclonal antibody therapy of cancer

Adams, Gregory P.; Weiner, Louis M.

doi:10.1038/nbt1137

Cited by 1,065 publications

(754 citation statements)

References 99 publications

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“…EGF is a critical regulator of cell survival responses and downstream signaling events leading to cell survival, thus making it an attractive target for disease therapy [37,40]. Several monoclonal antibodies or small molecule inhibitors directed against EGFR have been successfully used in cancer therapy [41,42]. Our findings herein suggest that the inhibition of EGFR, either as a stand-alone therapy or in combination with other approaches, might be a good approach for the treatment of granulosa cell proliferation dysfunction, granulosa cell tumors or other cancers that exhibit elevated HOX gene expression.…”

Section: Discussionmentioning

confidence: 99%

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Huang

Cheng

Nishi³

et al. 2010

Reprod Biol Endocrinol

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BackgroundHomeobox (HOX) genes encode transcription factors, which regulate cell proliferation, differentiation, adhesion, and migration. The deregulation of HOX genes is frequently associated with human reproductive system disorders. However, knowledge regarding the role of HOX genes in human granulosa cells is limited.MethodsTo determine the role of HOXA7 in the regulation and associated mechanisms of cell proliferation in human granulosa cells, HOXA7 and epidermal growth factor receptor (EGFR) expressions were examined in primary granulosa cells (hGCs), an immortalized human granulosa cell line, SVOG, and a granulosa tumor cell line, KGN, by real-time PCR and Western blotting. To manipulate the expression of HOXA7, the HOXA7 specific siRNA was used to knockdown HOXA7 in KGN. Conversely, HOXA7 was overexpressed in SVOG by transfection with the pcDNA3.1-HOAX7 vector. Cell proliferation was measured by the MTT assay.ResultsOur results show that HOXA7 and EGFR were overexpressed in KGN cells compared to hGCs and SVOG cells. Knockdown of HOXA7 in KGN cells significantly decreased cell proliferation and EGFR expression. Overexpression of HOXA7 in SVOG cells significantly promoted cell growth and EGFR expression. Moreover, the EGF-induced KGN proliferation was abrogated, and the activation of downstream signaling was diminished when HOXA7 was knocked down. Overexpression of HOXA7 in SVOG cells had an opposite effect.ConclusionsOur present study reveals a novel mechanistic role for HOXA7 in modulating granulosa cell proliferation via the regulation of EGFR. This finding contributes to the knowledge of the pro-proliferation effect of HOXA7 in granulosa cell growth and differentiation.

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Section: Discussionmentioning

confidence: 99%

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Huang

Cheng

Nishi³

et al. 2010

Reprod Biol Endocrinol

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“…Investigations into the mechanism of action for therapeutic antibodies, such as rituximab (anti-CD20) and herceptin (anti-erbB2), which have been used successfully in the clinic, have lead to an increasing appreciation of NK cell-mediated ADCC [4,5]. Several receptors, which activate antibody-independent, natural cytotoxicity are also associated with ITAM-containing signaling adaptors (Table 1).…”

Section: Activating Receptorsmentioning

confidence: 99%

Line of attack: NK cell specificity and integration of signals

Bryceson

Long

2008

Current Opinion in Immunology

182

161

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SummaryNatural killer (NK) cells possess potent cytolytic activity and secrete immune modulating cytokines. The large repertoire of NK cell receptors provides versatility for the identification of infected and transformed cells, and for their elimination by NK cells. NK cell responses also stimulate and regulate the adaptive arm of the immune system. We review current knowledge about the molecular specificity of NK cell receptors and about regulation of NK cell effector functions upon encounter with target cells. Mechanisms of recognition, interplay among receptors, signal integration, and dynamic finetuning of NK cell responses are discussed. New insights into molecular checkpoints for NK cell effector function are highlighted and underlying reasons for the complexity in NK cell recognition and signaling are proposed.

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“…Targeting HSPs may in principle be accomplished both by injection of purified HSPs, as well as with drugs (such as bortezomib, anthracyclines) that induce these genes [18,19]. Similarly, FcγR signaling may impact the efficacy of anti-tumor antibodies in cancer and provide novel approaches to improve their efficacy by antibody engineering [56].…”

Section: Discussionmentioning

confidence: 99%

Role of chaperones and FcγR in immunogenic death

Dhodapkar

2008

Current Opinion in Immunology

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Cell death under physiologic conditions does not lead to the induction of immunity. However recognition of stressed or opsonized cells can trigger immune responses. Recent studies have begun to illustrate the critical role of molecular chaperones such as inducible heat shock proteins in mediating immunogenicity of stressed cells. Immunity to opsonized cells depends in part on the engagement and the balance of activating and inhibitory FcγRs on antigen presenting dendritic cells. Understanding both these pathways of immunogenic cell death may yield novel approaches to regulate immunity. Two forms of immunogenic cell deathBillions of cells die each day and are replaced by newly differentiated progeny. Corpses of such dying cells are rapidly removed by phagocytes; do not elicit immunity and may induce tolerance. However under some settings, recognition of dying cells leads to inflammatory responses and immunity[1] • . Two aspects of such "immunogenic death" are the focus of this review. A common response to cellular stress is the transcriptional activation of molecular chaperones that belong to the class of inducible heat shock proteins (HSPs). Another setting wherein dying cells might induce immunity is when they are opsonized by antibodies due to antibody mediated recognition of determinants on dying cells. Such opsonized cells can be recognized by FcγR mediated pathways on antigen presenting cells (APCs). Below, we will discuss recent insights into how both of these pathways play an important role in regulating immunogenicity of dying cells and can be dysregulated in autoimmunity. Heat shock proteins (HSPs) and immunogenic cell deathHSPs are referred to as stress proteins or molecular chaperones, although most HSPs are constitutively expressed. Known best for their roles in regulating intracellular protein homeostasis, HSPs were immunologically implicated because of the observations that tumor-derived HSPs, although having no tumor-specific mutations, can immunize for tumor-specific T cell immunity [2] • . Efforts to explain the phenomenon have led to two

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Monoclonal antibody therapy of cancer

Cited by 1,065 publications

References 99 publications

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells

Line of attack: NK cell specificity and integration of signals

Role of chaperones and FcγR in immunogenic death

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