ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients.

Identification and reversal of treatment resistance mechanisms of clinically refractory tumor cells is critical for successful cancer therapy. Here we show that ATP-binding cassette member B5 (ABCB5) identifies therapy-refractory tumor cells in colorectal cancer patients following fluorouracil (5-FU)-based chemoradiation therapy and provide evidence for a functional role of ABCB5 in colorectal cancer 5-FU resistance. Examination of human colon and colorectal cancer specimens revealed ABCB5 to be expressed only on rare cells within healthy intestinal tissue, whereas clinical colorectal cancers exhibited substantially increased levels of ABCB5 expression. Analysis of successive, patient-matched biopsy specimens obtained prior to and following neoadjuvant 5-FU-based chemoradiation therapy in a series of colorectal cancer patients revealed markedly enhanced abundance of ABCB5-positive tumor cells when residual disease was detected. Consistent with this finding, the ABCB5-expressing tumor cell population was also treatment refractory and exhibited resistance to 5-FU-induced apoptosis in a colorectal cancer xenograft model of 5-FU monotherapy. Mechanistically, short hairpin RNA-mediated ABCB5 knockdown significantly inhibited tumorigenic xenograft growth and sensitized colorectal cancer cells to 5-FU-induced cell killing. Our results identify ABCB5 as a novel molecular marker of therapy-refractory tumor cells in colorectal cancer patients and point to a need for consistent eradication of ABCB5-positive resistant tumor cell populations for more effective colorectal cancer therapy.

Contrast-enhanced ultrasound imaging of sentinel lymph nodes after peritumoral administration of Sonazoid in a melanoma tumor animal model.

OBJECTIVES: The purpose of this study was to compare lymphosonography (ie, contrast-enhanced ultrasound imaging [US] after interstitial injection of a US contrast agent) for the detection of sentinel lymph nodes (SLNs) in swine with naturally occurring melanoma tumors to lymphoscintigraphy using blue dye-guided surgical dissection as the reference standard. Also, we sought to determine if lymphosonography can be used to characterize SLNs. METHODS: Sixty-three swine with 104 melanomas were evaluated. Contrast-specific US was performed after peritumoral injection (1 mL dose) of Sonazoid (GE Healthcare, Oslo, Norway). Lymphoscintigraphy was performed after peritumoral injections of technetium Tc 99m sulfur colloid. Peritumoral injection of 1% Lymphazurin (Ben Venue Labs, Inc, Bedford, OH) was used to guide SLN resection. The accuracy of SLN detection with the two imaging modalities was compared using the McNemar test. The SLNs were qualitatively and quantitatively characterized as benign or malignant based on the lymphosonography results with histopathology and RNA analyses used as the reference standards. RESULTS: Blue dye-guided surgery identified 351 SLNs. Lymphosonography detected 293 SLNs and 11 false-positives, while lymphoscintigraphy detected 231 SLNs and 20 false-positives. The accuracy of SLN detection was 81.8% for lymphosonography, which was significantly higher than the 63.2% achieved with lymphoscintigraphy (P < .0001). The accuracy of lymphosonography for SLN characterization was 80%. When the size of the enhanced SLN was taken into consideration to characterize SLNs, the accuracy was 86%. CONCLUSIONS: Lymphosonography is statistically better than lymphoscintigraphy for the detection of SLNs in this animal model. The ability to use lymphosonography as a means to characterize SLNs as benign or malignant is limited.