Autocrine induction of invasive and metastatic phenotypes by the MIF-CXCR4 axis in drug-resistant human colon cancer cells.
Metastasis and drug resistance are major problems in cancer chemotherapy. The purpose of this work was to analyze the molecular mechanisms underlying the invasive potential of drug-resistant colon carcinoma cells. Cellular models included the parental HT-29 cell line and its drug-resistant derivatives selected after chronic treatment with either 5-fluorouracil, methotrexate, doxorubicin, or oxaliplatin. Drug-resistant invasive cells were compared with noninvasive cells using cDNA microarray, quantitative reverse transcription-PCR, flow cytometry, immunoblots, and ELISA. Functional and cellular signaling analyses were undertaken using pharmacologic inhibitors, function-blocking antibodies, and silencing by retrovirus-mediated RNA interference. 5-Fluorouracil- and methotrexate-resistant HT-29 cells expressing an invasive phenotype in collagen type I and a metastatic behavior in immunodeficient mice exhibited high expression of the chemokine receptor CXCR4. Macrophage migration-inhibitory factor (MIF) was identified as the critical autocrine CXCR4 ligand promoting invasion in drug-resistant colon carcinoma HT-29 cells. Silencing of CXCR4 and impairing the MIF-CXCR4 signaling pathways by ISO-1, pAb FL-115, AMD-3100, monoclonal antibody 12G5, and BIM-46187 abolished this aggressive phenotype. Induction of CXCR4 was associated with the upregulation of two genes encoding transcription factors previously shown to control CXCR4 expression (HIF-2alpha and ASCL2) and maintenance of intestinal stem cells (ASCL2). Enhanced CXCR4 expression was detected in liver metastases resected from patients with colon cancer treated by the standard FOLFOX regimen. Combination therapies targeting the CXCR4-MIF axis could potentially counteract the emergence of the invasive metastatic behavior in clonal derivatives of drug-resistant colon cancer cells.
Dessein
Anne-Frédérique
AF
INSERM U837, Centre de Recherche Jean-Pierre Aubert, place de Verdun, Lille F-59045, France.
Stechly
Laurence
L
Jonckheere
Nicolas
N
Dumont
Patrick
P
Monté
Didier
D
Leteurtre
Emmanuelle
E
Truant
Stéphanie
S
Pruvot
François-René
FR
Figeac
Martin
M
Hebbar
Mohamed
M
Lecellier
Charles-Henri
CH
Lesuffleur
Thécla
T
Dessein
Rodrigue
R
Grard
Georges
G
Dejonghe
Marie-José
MJ
de Launoit
Yvan
Y
Furuichi
Yasuhiro
Y
Prévost
Grégoire
G
Porchet
Nicole
N
Gespach
Christian
C
Huet
Guillemette
G
D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D020869:Gene Expression Profiling; D020868:Gene Silencing; D019073:HT29 Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010641:Phenotype; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
C527276:CXCR4 protein, human; D008263:Macrophage Migration-Inhibitory Factors; D009944:Organoplatinum Compounds; D019718:Receptors, CXCR4; D000077150:Oxaliplatin; D004317:Doxorubicin; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; D005472:Fluorouracil; D008727:Methotrexate