CXCL12 Retargeting of an Oncolytic Adenovirus Vector to the Chemokine CXCR4 and CXCR7 Receptors in Breast Cancer

Abstract

Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant progress has been made in developing targeted therapies for breast cancer, advanced breast cancer continues to have high mortality, with poor 5-year survival rates. Thus, current therapies are insufficient in treating advanced stages of breast cancer; new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We showed that the modified virus targets and infects CXCR4-and CXCR7overexpressing breast cancer cells more efficiently than a wild-type control vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the results of this study demonstrate the feasibility of retargeting adenovirus vectors to chemokine receptor-positive tumors.

Evaluation of the influence of the C-X-C motif chemokine ligand 12 / C-X-C chemokine receptor 4 axis on canine mammary gland tumor cell migration

“…Furthermore, a human breast cancer cell line, MCF-7, showed low expression of CXCR4 and slower tumor growth than that of the CXCR4 high-expression cell line, MDA-MB-231 [ 6 , 18 ]. In another study, CXCR4 expression was examined by western blotting in six human breast cancer cell lines and was found to be positive in all [ 20 ]. In a study on canine osteosarcoma and hemangiosarcoma cell lines that examined CXCR4 expression, all five osteosarcoma cell lines and two of four hemangiosarcoma cell lines were CXCR4-positive [ 7 , 11 ].…”

“…We determined that the significant decrease in the percentage of the wounded area filled by pre-treatment with AMD3100 was due to CXCL12/CXCR4 axis inhibition since no cytotoxicity was observed in a study using AMD3100 at concentrations 30 times higher than those used in this study [ 14 ]. CXCR7, a structurally related chemokine receptor, is capable of binding to CXCL12 [ 20 , 23 ]. CXCR7 is overexpressed in human breast cancer cells [ 16 , 20 ] and is implicated in driving tumor cell initiation, survival, progression, and metastasis [ 2 , 10 ].…”

“…CXCR7, a structurally related chemokine receptor, is capable of binding to CXCL12 [ 20 , 23 ]. CXCR7 is overexpressed in human breast cancer cells [ 16 , 20 ] and is implicated in driving tumor cell initiation, survival, progression, and metastasis [ 2 , 10 ]. We suggest that the increase in migratory ability is caused by the CXCL12/CXCR4 axis since AMD3100 is a CXCR4 antagonist and does not inhibit CXCR7.…”

Phage‐Derived Oncolytic Viruses with 3C from Seneca Valley Virus for Targeted Therapy of Cervical Cancer

“…The same problem widely exists with the used oncolytic viruses (adenoviruses and adeno‐associated viruses). [ 34 ] Numerous studies have attempted to improve the delivery of viruses in vivo after intravenous administration with the help of liposomes, nanoparticles, and immune cells. [ 35 ] To improve the treatment's efficacy of this oncolytic viruses, the recombinant phage should be modified to extend its circulation time in vivo in next step.…”

Construction and application of adenoviral vectors

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