JAMA Otol Logo Orlando 2013 AHNS Meeting Location
American Head & Neck Society
Annual Meeting, April 10-11, 2013
JW Marriott Grande Lakes
Orlando, Florida

During the
Combined Otolaryngology Spring Meeting
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Presentation: S028
Topic: Basic Science - Molecular Targets/ Exp. Therapeutics
Type: Oral Presentation
Date: Thursday, April 11, 2013
Session: 03:45 PM - 04:45 PM Basic Science
Authors: Joel Y Sun, Joel Thibodeaux, Gang Huang, Yiguang Wang, Jingming Gao, Philip S Low, Baran D Sumer
Institution(s): University of Texas Southwestern Medical Center; Purdue University

Objective: The folate receptor (FR) is a high-affinity folic acid binding endocytic receptor uncommonly expressed in normal tissues. The alpha isoform is overexpressed in a variety of epithelial neoplastic cells. In contrast, functional expression of the beta isoform is limited to activated macrophages. Importantly, in many malignancies FR serves as a convenient target for the delivery of tumor specific drugs and imaging markers. Folic acid conjugated fluorescent dyes have been used to guide tumor resection in mouse models and more recently in humans. However, their potential in HNSCC is unclear due to reported differential FR expression and an incomplete characterization of FR expression in tumors. We hypothesized that tumor infiltrating macrophages expressing FR-beta could allow fluorescent visualization of HNSCC tumors using folate conjugated dyes even when FR expression in cancer cells is low.

Study Design: In vivo animal study and retrospective review of clinical pathologic specimens.

Setting: Academic tertiary referral center.

Subjects and Methods: Immunohistochemistry was performed on a tissue microarray (TMA) containing primary tumor tissue and matched tumor free surgical margins from 22 patients who underwent HNSCC resection. Primary tumor sites included the oral tongue, base of tongue, tonsil, supraglottic larynx, glottic larynx and hypopharynx. We evaluated the expression of FR-alpha, FR-beta, transforming growth factor- beta (TGF-B), the macrophage marker CD68 and the alternatively activated macrophage marker arginase-1 using appropriate positive and negative controls for staining. Orthotopic xenograft tumor models were generated by injecting HN5 and FaDu HNSCC cell lines into the submental triangle of nude mice. The mice received 0.8 mg/kg intravenous injections of fluorescein isothiocyanate conjugated folate (Folate-FITC) and were imaged for fluorescent emission under 495nm light two hours later. Mouse tissues were then sectioned for examination using fluorescent microscopy.

Results: No FR-alpha expression was observed in any TMA tumor or normal tissue specimen. All tumor samples demonstrated strongly positive FR-beta expression. Cellular morphology and CD68 expression identified the FR-beta expressing cells as tumor infiltrating macrophages. No association was observed between FR-beta staining and TGF-B or arginase-1 staining. In the xenograft models, tumors showed strong fluorescence in vivo after folate-FITC injection. Normal salivary glands and surrounding neck muscles did not demonstrate significant fluorescence. Histologic examination of the mouse xenografts revealed that fluorescence within the tumors was confined to areas of inflammatory cell infiltration and necrosis, consistent with our TMA data.

Conclusion: HNSCC tumors contain a significant population of FR-beta expressing macrophages. In contrast to many other carcinomas, the HNSCC tumor cells in our TMA did not express FR-alpha. Despite this, folate conjugated FITC dye was able to target and specifically label tumor xenografts in mice due to the FR-beta expression on infiltrating macrophages, allowing macroscopic fluorescence imaging. Thus, the folate linked delivery of fluorescent dye into the tumor microenvironment can facilitate image guided surgery even when HNSCC tumor cells themselves do not express FR.

Fluorescent image of mouse xenograft exhibiting labeling of the tumor with folate-FITC.

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