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AXL is a key regulator of inherent and chemotherapy-induced invasion and predicts a poor clinical outcome in early-stage colon cancer

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  • Purpose: Despite The Use Of 5-Fluorouracil (5-Fu)–Based Adjuvant Treatments
  • A Large Proportion Of Patients With High-Risk Stage Ii/Iii Colorectal Cancer Will Relapse
  • Thus
  • Novel Therapeutic Strategies Are Needed For Early-Stage Colorectal Cancer
  • Residual Micrometastatic Disease From The Primary Tumor Is A Major Cause Of Patient Relapse
  • <Br/><Br/>Experimental Design: To Model Colorectal Cancer Tumor Cell Invasion/Metastasis
  • We Have Generated Invasive (Krasmt/Kraswt/+Chr3/P53-Null) Colorectal Cancer Cell Subpopulations
  • Receptor Tyrosine Kinase (Rtk) Screens Were Used To Identify Novel Proteins That Underpin The Migrat
  • Migration/Invasion Was Assessed Using The Xcelligence System
  • Tumors From Patients With Early-Stage Colorectal Cancer (N = 336) Were Examined For Axl Expression
  • <Br/><Br/>Results: Invasive Colorectal Cancer Cell Subpopulations Showed A Transition From An Epithe
  • Invasion
  • Colony-Forming Ability
  • And An Attenuation Of Egf Receptor (Egfr)/Her2 Autocrine Signaling
  • Rtk Arrays Showed Significant Increases In Axl Levels In All Invasive Sublines
  • Importantly
  • 5-Fu Treatment Resulted In Significantly Increased Migration And Invasion
  • And Targeting Axl Using Pharmacologic Inhibition Or Rna Interference (Rnai) Approaches Suppressed Ba
  • Significantly
  • High Axl Mrna And Protein Expression Were Found To Be Associated With Poor Overall Survival In Early
  • <Br/><Br/>Conclusions: We Have Identified Axl As A Poor Prognostic Marker And Important Mediator Of
  • These Findings Provide Support For The Further Investigation Of Axl As A Novel Prognostic Biomarker
  • In Particular In The Adjuvant Disease In Which Egfr/Vegf–Targeted Therapies Have Failed
  • Biology


Chapter 2 Androgen Action During Prostate Carcinogenesis Diping Wang and Donald J. Tindall Abstract Androgens are critical for normal prostate development and function, as well as prostate cancer initiation and progression. Androgens function mainly by regulating target gene expression through the androgen receptor (AR). Many studies have shown that androgen-AR signaling exerts actions on key events during prostate carcinogenesis. In this review, androgen action in distinct aspects of prostate carcinogenesis, including (i) cell proliferation, (ii) cell apoptosis, and (iii) prostate cancer metastasis will be discussed. Key words: Androgen receptor, prostate cancer, androgen metabolism, androgen signaling, castration-resistant prostate cancer. 1. Androgen Signaling Androgens are the male sex hormones, which control the differ- entiation and maturation of male reproductive organs, including the prostate gland. Testosterone is the principal androgen in cir- culation and is synthesized by Leydig cells in the testes, under the regulation of luteinizing hormone (LH), which is further regulated by gonadotropin-releasing hormone (GnRH). Adrenal glands also synthesize a small amount of androgens, such as dehy- droepiandrosterone (DHEA) and androstenedione (4-dione) (1). Testosterone enters prostate cells by passive diffusion, where it is converted enzymatically by 5-α reductases to the more potent androgen dihydrotestosterone (DHT) (2). Binding of androgens to the androgen receptor (AR), a ligand-modulated transcrip- tion factor, induces a conformational change in the AR, causing release of heat shock proteins and translocation of the AR to the F. Saatcioglu (ed.), Androgen Action, Methods in Molecular Biology 776, DOI 10.1007/978-1-61779-243-4_2, © Springer Science+Business Media, LLC 2011 25 26 Wang and Tindall nucleus, where it transcriptionally regulates the expression of tar- get genes (3). In addition to the classic genomic effects of sex steroids, accu- mulating

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