Dynamic contrast-enhanced MRI evaluates the early response of human head and neck tumor xenografts following anti-EMMPRIN therapy with cisplatin or irradiation

Abstract

Purpose: To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease inducer) antibody with/without cisplatin or X-ray radiation in head and neck cancer mouse models using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Materials and methods: Mice bearing SCC1 (or OSC19) tumor xenografts were treated with anti-EMMPRIN antibody, radiation, cisplatin, or anti-EMMPRIN antibody plus cisplatin (or radiation) for a week (n = 4-5 per group). DCE-MRI was carried out on a 9.4T small animal MR scanner on days 0, 3, and 7, and K(trans) values were averaged in a 0.5-mm-thick peripheral tumor region. Ki67 and CD31 staining were implemented for all tumors after imaging.

Results: The K(trans) changes of SCC1 and OSC19 tumors treated with anti-EMMPRIN antibody for 3 days were -18 ± 8% and 4 ± 7%, respectively, which were significantly lower than those of control groups (39 ± 5% and 45 ± 7%; P = 0.0025 and 0.0220, respectively). When cisplatin was added, those were -42 ± 9% and -44 ± 9%, respectively, and with radiation, -45 ± 9% and -27 ± 10%, respectively, which were also significantly lower than those of control groups (P < 0.0001 for all four comparisons). In the eight groups untreated (served as control) or treated with anti-EMMPRIN antibody with/without cisplatin or radiation, the mean K(trans) change for 3 days was significantly correlated with the mean tumor volume change for 7 days (r = 0.74, P = 0.0346), Ki67-expressing cell density (r = 0.96, P = 0.0001), and CD31 density (r = 0.84, P = 0.0084).

Conclusion: DCE-MRI might be utilized to assess the early therapeutic effects of anti-EMMPRIN antibody with/without chemotherapy or radiotherapy in head and neck cancer.

Keywords: DCE-MRI; anti-EMMPRIN antibody; cisplatin; head and neck cancer; radiotherapy.

Figure 1

MR contrast maps at 2, 10, and 40 minutes after gadoteridol injection, and K^trans maps in entire tumor region or 0.5-mm thick peripheral tumor region of representative (a) SCC1 and (b) OSC19 tumors prior to therapy initiation. Contrast enhancement curves averaged in the four pixels indicated with solid white box in each contrast map are shown.

Figure 2

K^trans change in 0.5-mm thick peripheral tumor region and tumor volume change in two human head and neck cancer mouse models. (a, b) K^trans change in 0.5-mm thick peripheral region of (a) SCC1 and (b) OSC19 tumors for 3 and 7 days after therapy initiation. (c, d) Volume change of (c) SCC1 and (d) OSC19 tumors for 3 and 7 days after therapy initiation. Six groups of animals (n=4–5 per group) were untreated (served as control) or treated with anti-EMMPRIN antibody (EMMP), cisplatin, X-ray irradiation, anti-EMMPRIN antibody plus cisplatin (EMMP+Cis), and anti-EMMPRIN antibody plus X-ray irradiation (EMMP+X), respectively. Asterisk and hash mark represent statistical difference from control and anti-EMMPRIN treated groups, respectively.

Figure 3

Histological analyses of SCC1 tumors. (a) Representative microphotographs of Ki67 and CD31 stained tumor slices (5 µm thickness), when tumors were untreated (control) or treated with anti-EMMPRIN antibody (EMMP), cisplatin, X-ray irradiation, anti-EMMPRIN antibody plus cisplatin (EMMP+Cis), and anti-EMMPRIN antibody plus X-ray irradiation (EMMP+X), respectively. Ki67 expressing (proliferating) and CD31 stained (endothelial) cells are indicated with black arrows, and the length of each scale bar is 0.1 mm. (b) Ki67 expressing cell and (c) CD31 densities (mean±SE). Asterisk represents statistical difference from control group.

Figure 4

Histological analyses of OSC19 tumors. (a) Representative microphotographs of Ki67 and CD31 stained tumor slices (5 µm thickness), when tumors were untreated (control) or treated with anti-EMMPRIN antibody (EMMP), cisplatin, X-ray irradiation, anti-EMMPRIN antibody plus cisplatin (EMMP+Cis), and anti-EMMPRIN antibody plus X-ray irradiation (EMMP+X), respectively. Ki67 expressing (proliferating) and CD31 stained (endothelial) cells are indicated with black arrows, and the length of each scale bar is 0.1 mm. (b) Ki67 expressing cell and (c) CD31 densities (mean±SE). Asterisk and hash mark represent statistical difference from control and anti-EMMPRIN treated groups, respectively.

Figure 5

Correlation between the mean tumor K^trans change (either for 3 days or 7 days) and the mean tumor volume change for 7 days (or histological findings). A total of 12 groups (6 groups per each tumor type) were untreated (served as control) or treated with anti-EMMPRIN antibody, cisplatin, X-ray irradiation, anti-EMMPRIN antibody plus cisplatin, and anti-EMMPRIN antibody plus X-ray irradiation. Data of SCC1 tumors treated with X-radiation monotherapy were indicated with black diamonds, while the others were with gray circles. Pearson correlation coefficients and p values were found when X-ray treated SCC1 data were included (listed above) or excluded (listed below).