CCL5 neutralization restricts cancer growth and potentiates the targeting of PDGFRβ in colorectal carcinoma.
Increased CCL5 levels are markers of an unfavourable outcome in patients with melanoma, breast, cervical, prostate, gastric or pancreatic cancer. Here, we have assessed the role played by CCL5/CCR5 interactions in the development of colon cancer. To do so, we have examined a number of human colorectal carcinoma clinical specimens and found CCL5 and its receptors over-expressed within primary as well as liver and pulmonary metastases of patients compared to healthy tissues. In vitro, CCL5 increased the growth and migratory responses of colon cancer cells from both human and mouse origins. In addition, systemic treatment of mice with CCL5-directed antibodies reduced the extent of development of subcutaneous colon tumors, of liver metastases and of peritoneal carcinosis. Consistently, we found increased numbers of CD45-immunoreactive cells within the stroma of the remaining lesions as well as at the interface with the healthy tissue. In contrast, selective targeting of CCR5 through administration of TAK-779, a CCR5 antagonist, only partially compromised colon cancer progression. Furthermore, CCL5 neutralization rendered the tumors more sensitive to a PDGFRβ-directed strategy in mice, this combination regimen offering the greatest protection against liver metastases and suppressing macroscopic peritoneal carcinosis. Collectively, our data demonstrate the involvement of CCL5 in the pathogenesis of colorectal carcinoma and point to its potential value as a therapeutic target.
Université de Nice Sophia Antipolis, UFR Médecine, Nice, France. cambien@unice.fr
Béatrice
B
Cambien
Peggy
P
Richard-Fiardo
Babou F
BF
Karimdjee
Violette
V
Martini
Bernard
B
Ferrua
Bruno
B
Pitard
Heidy
H
Schmid-Antomarchi
Annie
A
Schmid-Alliana
D000577:Amides / Q000494:pharmacology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006224:Cricetinae; D003412:Cricetulus; D018450:Disease Progression; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000378:metabolism; D016896:Treatment Outcome
D000577:Amides; D057134:Antibodies, Neutralizing; D018946:Chemokine CCL5; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; C119369:TAK 779; D020797:Receptor, Platelet-Derived Growth Factor beta