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. 2016 Dec 20;7(51):85185-85195.
doi: 10.18632/oncotarget.13238.

CXCR4 antagonists suppress small cell lung cancer progression

Sanaz Taromi  1 , Gian Kayser  2 , Julie Catusse  1 , Dominik von Elverfeldt  3 , Wilfried Reichardt  3 , Friederike Braun  4   5   6 , Wolfgang A Weber  4   5 , Robert Zeiser  1 , Meike Burger  1   7
Affiliations

CXCR4 antagonists suppress small cell lung cancer progression

Sanaz Taromi et al. Oncotarget. .

Abstract

Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis due to early metastatic spread and development of chemoresistance. Playing a key role in tumor-stroma interactions the CXCL12-CXCR4 axis may be involved in both processes and thus represent a promising therapeutic target in SCLC treatment. In this study we investigated the effect of CXCR4 inhibition on metastasis formation and chemoresistance using an orthotopic xenograft mouse model. This model demonstrates regional spread and spontaneous distant metastases closely reflecting the clinical situation in extensive SCLC. Tumor engraftment, growth, metabolism, and metastatic spread were monitored using different imaging techniques: Magnetic Resonance Imaging (MRI), Bioluminescence Imaging (BLI) and Positron Emission Tomography (PET). Treatment of mice bearing chemoresistant primary tumors with the specific CXCR4 inhibitor AMD3100 reduced the growth of the primary tumor by 61% (P<0.05) and additionally suppressed metastasis formation by 43%. In comparison to CXCR4 inhibition as a monotherapy, standard chemotherapy composed of cisplatin and etoposide reduced the growth of the primary tumor by 71% (P<0.01) but completely failed to suppress metastasis formation. Combination of chemotherapy and the CXCR4 inhibitor integrated the highest of both effects. The growth of the primary tumor was reduced to a similar extent as with chemotherapy alone and metastasis formation was reduced to a similar extent as with CXCR4 inhibitor alone. In conclusion, we demonstrate in this orthotopic mouse model that the addition of a CXCR4 inhibitor to chemotherapy significantly reduces metastasis formation. Thus, it might improve the overall therapy response and consequently the outcome of SCLC patients.

Keywords: AMD3100; CXCL12; metastasis; mouse model; small cell lung cancer.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. CXCR4 antagonists inhibit CXCL12-induced cell migration
A. Migration of SCLC cells towards CXCL12 gradient was evaluated by a 3D chemotaxis assay. The bars represent the mean relative migration of cells towards different CXCL12 concentrations ±SD (n=3). B. Cells were treated with PBS or the CXCR4 inhibitors TN14003 (5 μM) or AMD3100 (100 nM). The bars represent the mean relative migration of cells towards CXCL12 (1000 ng/ml) ±SD (n=3). The corresponding trajectories on the right panel illustrate the covered distance at the x axis.
Figure 2
Figure 2. AMD3100 reduces the growth of the primary tumor and metastasis formation
A. Tumor-bearing mice were treated twice a day with PBS vehicle control or 2.5 mg/kg AMD3100, starting at day 14 after tumor inoculation (control group n=7; treated group n=6). Treatment continued for five weeks. One representative result out of three independent experiments is shown. The corresponding MR images are illustrated on the right panel. B. Treatment with AMD3100 reduces the progression of vital tumor cells at the terminal point. Right panel: representative BL images of control and AMD3100-treated mice at indicated time points. C. PET scan analysis displayed no difference in metabolic activity of tumor cells in the control (n=3) and AMD3100-treated group (n=3). D. AMD3100 treatment suppresses formation of metastases. Data are shown as percentage of mice which developed spontaneous metastases (treated group n=11 and controls n=10).
Figure 3
Figure 3. Chemotherapy reduces the growth of the primary tumor, but does not affect metastasis formation
A. Mice were treated with a combination of etoposide and cisplatin (n=7) or PBS vehicle control (n=6) at day 14 and 21 after tumor inoculation. One representative result out of two separate experiments is shown. The corresponding MR images are illustrated on the right panel. B. Progression of vital tumor cells in control and chemotherapy-treated group at a terminal time point. Right panel: representative BL images from the day of tumor cell injection up to week 7. C. Metabolic activity of tumor cells was analyzed using PET scan. Chemotherapy reduced FDG-uptake of tumor cells by 58% (n=3) and FET-uptake by 34% (n=3). D. Chemotherapy did not affect metastasis formation. Data are shown as a percentage of mice which developed metastases (control group n=6; treated group n=7).
Figure 4
Figure 4. Combination of chemotherapy and AMD3100 shows antimetastatic effect
A. At days 14 and 21 after tumor inoculation Rag2-/-γc-/- mice were treated with a combination of cisplatin (5 mg/kg body weight) and etoposide (30 mg/kg body weight). Starting 2 weeks after inoculation, animals were additionally treated twice a day with PBS or 2.5 mg/kg AMD3100 for five weeks (control group n=9; treated group n=9). No difference in the growth of primary tumors was observed. B. Progression of vital tumor cells and representative evaluation of the BLI in chemotherapy and combination group. C. PET scan analysis displayed equal uptake of radiotracers in both groups (n=3 per group). D. Effect of AMD3100 addition on the formation of metastases. Data are shown as percentage of mice showing spontaneous metastases (n=7 per group).
Figure 5
Figure 5. Representative images of CXCR4 (red) and CXCL12 (brown) immunohistochemical double staining on primary tumors and metastases
CXCR4 is heterogeneously expressed within the specimens. Expression of CXCR4 is suppressed upon chemotherapy treatment. CXCL12 is predominantly localized in the cytoplasm of SCLC cells. No significant changes in CXCL12 and CXCR4 expression were detected between treated and control groups (n=7-13 per group).
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