Targeting CXCR4 with CTCE-9908 inhibits prostate tumor metastasis
Donald Wong, Pridvi Kandagatla, Walter Korz
1Department of Urology, Wayne State University School of Medicine, 9200 Scott Hall 540 E, Canfield Avenue, Detroit, MI 48201, USA. schinni@med.wayne.edu.
Background:
CXCL12/CXCR4 transactivation of epidermal growth factor family receptors in lipid raft membrane microdomains on cell surface is thought to mediate tumor growth and subsequent development of metastatic disease. CTCE-9908 is a known inhibitor of CXCR4. Herein, we tested the efficacy of CTCE-9908 in inhibiting prostate cancer cell growth, invasion, and metastasis.
Methods:
We used a panel of in vitro assays utilizing human prostate cancer cell lines and an in vivo orthotopic prostate cancer model to assess the anti-tumoral activity of CTCE-9908.
Results:
We demonstrated that (a) CTCE-9908 treatment resulted in no significant change in the growth of PC-3 and C4-2B cells; (b) 50 μg/ml of CTCE-9908 inhibited the invasive properties of PC-3 cells; (c) 25 mg/kg of CTCE-9908 did not alter primary tumor growth but it did significantly reduce total tumor burden in the animal including the growth of prostate and soft tissue metastases to lymph node and distant organ tissues. Histological analysis showed that CTCE-9908 treatment resulted in tumor necrosis in primary prostate tumors and no significant change in proliferation of tumor cells as measured by Ki-67 staining; (d) CTCE-9908 inhibited the tumor angiogenesis as measured by CD34 positive vessels in tumors.
Conclusions:
These data suggest that CXCR4 inhibition by CTCE-9908 decreases the invasion potential in vitro, which then translated to a reduction of tumor spread with associated reduction in angiogenesis. Hence, CTCE-9908 may prove to be an efficacious novel agent to prevent and treat the spread of metastatic prostate cancer.
Insights
CTCE-9908, a CXCR4 inhibitor, reduced prostate cancer cell invasion and metastasis in vivo. While not affecting primary tumor growth, it decreased overall tumor burden and angiogenesis, suggesting potential for treating metastatic prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- CXCL12/CXCR4 signaling promotes tumor growth and metastasis via epidermal growth factor receptor transactivation.
- Lipid raft microdomains are critical for this signaling pathway on the cell surface.
- CTCE-9908 is a known inhibitor of CXCR4.
Purpose of the Study:
- To evaluate the efficacy of CTCE-9908 in inhibiting prostate cancer cell growth, invasion, and metastasis.
- To assess the anti-tumoral activity of CTCE-9908 in vitro and in vivo.
Main Methods:
- Utilized in vitro assays with human prostate cancer cell lines (PC-3, C4-2B).
- Employed an in vivo orthotopic prostate cancer model in animals.
- Assessed tumor growth, invasion, metastasis, proliferation (Ki-67), and angiogenesis (CD34).
Main Results:
- CTCE-9908 did not significantly alter PC-3 and C4-2B cell growth.
- Inhibited invasive properties of PC-3 cells at 50 μg/ml.
- Reduced overall tumor burden and spread to lymph nodes and distant organs at 25 mg/kg, with tumor necrosis observed.
- Inhibited tumor angiogenesis, indicated by reduced CD34 positive vessels.
Conclusions:
- CXCR4 inhibition by CTCE-9908 reduces prostate cancer cell invasion in vitro.
- Translates to decreased tumor spread and angiogenesis in vivo.
- CTCE-9908 shows promise as a novel therapeutic agent for metastatic prostate cancer.
