Conrad, F, Zhu, X, Zhang, X, Chalkley, RJ, Burlingame, AL, Marks, JD et al.. Human antibodies targeting cell surface antigens overexpressed by the hormone refractory metastatic prostate cancer cells: ICAM-1 is a tumor antigen that mediates prostate cancer cell invasion. J Mol Med 87: 507-514

UCSF Helen Diller Family Comprehensive Cancer Center San Francisco CA 94110 USA
Journal of Molecular Medicine (Impact Factor: 5.11). 05/2009; 87(5):507-514. DOI: 10.1007/s00109-009-0446-3
Source: PubMed


Transition from hormone-sensitive to hormone-refractory metastatic tumor types poses a major challenge for prostate cancer
treatment. Tumor antigens that are differentially expressed during this transition are likely to play important roles in imparting
prostate cancer cells with the ability to grow in a hormone-deprived environment and to metastasize to distal sites such as
the bone and thus, are likely targets for therapeutic intervention. To identify those molecules and particularly cell surface
antigens that accompany this transition, we studied the changes in cell surface antigenic profiles between a hormone-sensitive
prostate cancer line LNCaP and its hormone-refractory derivative C4-2B, using an antibody library-based affinity proteomic
approach. We selected a naïve phage antibody display library to identify human single-chain antibodies that bind specifically
to C4-2B but not LNCaP. Using mass spectrometry, we identified one of the antibody-targeted antigens as the ICAM-1/CD54/human
rhinovirus receptor. Recombinant IgG1 derived from this single-chain antibody binds to a neutralizing epitope of ICAM-1 and
blocks C4-2B cell invasion through extracellular matrix in vitro. ICAM-1 is thus differentially expressed during the transition
of the hormone-sensitive prostate cancer cell line LNCaP to its hormone-refractory derivative C4-2B, plays an important role
in imparting the C4-2B line with the ability to invade, and may therefore be a target for therapeutic intervention.

KeywordsHormone refractory metastatic prostate cancer-Mass spectrometry-LNCaP-C4-2B-ICAM-1/CD54/rhinovirus receptor-Human single-chain antibodies-Neutralizing human IgG

Download full-text


Available from: Alma L Burlingame
  • Source
    • "Cell-surface integrins on circulating blood cells and cancer cells often interact with cell adhesion molecules expressed on endothelial cells such as VCAMs and ICAMs (Steiner et al., 2010). Among these, interaction between integrin a v b 3 and ICAM-1 is the best characterized (Conrad et al., 2009). Our data indicated that pre-treatment with simvastatin significantly impaired the ability of PC3 cells to recognize and adhere to human soluble ICAM-1, thus demonstrating the direct effect of simvastatin on inhibiting interactions of prostate cancer cells with cellular adhesion molecules. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer micrometastasis relies on the ability of cancer cells to secrete angiogenic modulators, to interact with the vascular endothelium, and to overcome the resistance offered by the endothelial-barrier. Being an essential step prior to metastasis, blockage of micrometastasis can have potential applications in cancer therapy and metastasis prevention. Due to poorly known molecular mechanisms leading to micrometastasis, developing therapeutic strategies to target prostate cancer utilizing drugs that block micrometastasis is far from reality. Here we demonstrate the potential benefits of simvastatin in the inhibition of prostate cancer micrometastasis and reveal the novel molecular mechanisms underlying this process. First, we showed that simvastatin inhibited the ability of human PC3 prostate cancer cells for transendothelial migration in vitro. Second, our data indicated that simvastatin modulates the expression of tumor derived factors such as angiopoietins and VEGF-A at the mRNA and protein levels by the PC3 cells, thus preventing endothelial-barrier disruption. Third, simvastatin directly activated endothelial cells and enhances endothelial-barrier resistance. Apart from this, our study revealed that simvastatin-mediated effect on PC3 micrometastasis was mediated through inhibition of integrin αv β3 activity and suppression of interaction between prostate cancer cell integrin αv β3 with endothelial ICAM-1. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2013 · Journal of Cellular Physiology
  • Source

    Preview · Article · Jan 2010
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human antibodies targeting prostate cancer cell surface epitopes may be useful for imaging and therapy. The objective of this study was to evaluate the tumor targeting of an internalizing human antibody fragment, a small-size platform, to provide high contrast in a mouse model of human prostate carcinoma. A prostate tumor-targeting single-chain antibody fragment (scFv), UA20, along with a nonbinding control scFv, N3M2, were labeled with (99m)Tc and evaluated for binding and rapid internalization into human prostate tumor cells in vitro and tumor homing in vivo using xenograft models. For the in vitro studies, the labeled UA20 scFv was incubated at 37 degrees C for 1 h with metastatic prostate cancer cells (DU145) to assess the total cellular uptake versus intracellular uptake. For the animal studies, labeled UA20 and N3M2 scFvs were administered to athymic mice implanted subcutaneously with DU145 cells. Mice were imaged with small-animal SPECT/CT with concomitant biodistribution at 1 and 3 h after injection. The UA20 scFv was labeled in 55%-65% yield and remained stable in phosphate buffer within 24 h. The labeled UA20 scFv was taken up specifically by prostate tumor cells. Internalization was rapid, because incubation at 37 degrees C for less than 1 h resulted in 93% internalization of total cell-associated scFvs. In animal studies, SPECT/CT showed significant tumor uptake as early as 1 h after injection. At 3 h after injection, tumor uptake was 4.4 percentage injected dose per gram (%ID/g), significantly greater than all organs or tissues studied (liver, 2.7 %ID/g; other organs or tissues, <1 %ID/g), except the kidneys (81.4 %ID/g), giving tumor-to-blood and tumor-to-muscle ratios of 12:1 and 70:1, respectively. In contrast, the control antibody exhibited a tumor uptake of only 0.26 %ID/g, similar to that of muscle and fat. Tumor-specific targeting was evidenced by reduced tumor uptake of nearly 70% on administration of a 10-fold excess of unlabeled UA20 scFv. Kidney uptake was nonspecific, consistent with the route of excretion by scFvs. The UA20 scFv showed rapid and specific internalization in prostate tumor cells in vitro and accumulation in prostate tumor xenografts in vivo, demonstrating the potential for future development for prostate cancer imaging and targeted therapy.
    Full-text · Article · Feb 2010 · Journal of Nuclear Medicine
Show more