Department of Biological Sciences, Purdue University, West Lafayette, IN 47907 USA.
Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907 USA.
The adjuvant therapy of choice for superficial bladder cancer is the intravesical instillation of live Mycobacterium bovis Bacillus Calmette-Guerin (BCG). In spite of the fact that this therapy is the most effective treatment for superficial bladder cancer, intravesical administration of BCG is associated with high local morbidity and the potential for systemic infection. Therefore, there is a need for the development of safer, less toxic approaches to fight this disease. Since fibronectin attachment protein (FAP) is a key element in BCG retention and targeting to cells, we hypothesize that this protein can be used as targeting agent to deliver cytotoxic cargo for the treatment of bladder tumors. Here we evaluated the ability of bladder tumor cells to bind and endocytose FAP via fibronectin-integrin complexes. We found that microaggregation induced by an anti-FAP polyclonal antibody accelerated FAP uptake by T24 bladder tumor cells. FAP was determined to be internalized via a clathrin-independent, caveolae-dependent mechanism. Further, once within the endosomal compartment, FAP was targeted to the lysosomal compartment with negligible recycling to the plasma membrane. Importantly, we demonstrated that FAP microaggregation and internalization could also be triggered by multivalent Ni(2+) NTA-bearing liposomes. Overall, our studies validate the use of FAP as a targeting vector and provide the foundation for the design of more effective, less toxic bladder cancer therapeutics.
Written by:
Coon BG, Crist S, González-Bonet AM, Kim HK, Sowa J, Thompson DH, Ratliff TL, Aguilar RC. Are you the author?
Reference: Int J Cancer. 2011 Sep 7. Epub ahead of print.
doi: 10.1002/ijc.26413
PubMed Abstract
PMID: 21901746
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