Thrombospondin-1 triggers cell migration and development of advanced prostate tumors.
The antitumor effects of pharmacologic inhibitors of angiogenesis are hampered in patients by the rapid development of tumor resistance, notably through increased invasiveness and accelerated metastasis. Here, we reevaluated the role of the endogenous antiangiogenic thrombospondin 1 (TSP1) in prostate carcinomas in which angiogenesis is an active process. In xenografted tumors, we observed that TSP1 altogether inhibited angiogenesis and fostered tumor development. Our results show that TSP1 is a potent stimulator of prostate tumor cell migration. This effect required CD36, which also mediates TSP1 antiangiogenic activity, and was mimicked by an antiangiogenic TSP1-derived peptide. As suspected for pharmacologic inhibitors of angiogenesis, the TSP1 capacities to increase hypoxia and to trigger cell migration are thus inherently linked. Importantly, although antiangiogenic TSP1 increases hypoxia in vivo, our data show that, in turn, hypoxia induced TSP1, thus generating a vicious circle in prostate tumors. In radical prostatectomy specimens, we found TSP1 expression significantly associated with invasive tumors and with tumors which eventually recurred. TSP1 may thus help select patients at risk of prostate-specific antigen relapse. Together, the data suggest that intratumor disruption of the hypoxic cycle through TSP1 silencing will limit tumor invasion.
CNRS, FRE3239, Université Paris Sud, Villejuif, France.
Virginie
V
Firlej
Jacques R R
JR
Mathieu
Cristèle
C
Gilbert
Loïc
L
Lemonnier
Jessica
J
Nakhlé
Catherine
C
Gallou-Kabani
Basma
B
Guarmit
Aurélie
A
Morin
Natalia
N
Prevarskaya
Nicolas Barry
NB
Delongchamps
Florence
F
Cabon
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009919:Orchiectomy; D010455:Peptides / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050916:TRPV Cation Channels / Q000378:metabolism; D019700:Thrombospondin 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D018955:CD36 Antigens; D010455:Peptides; D050916:TRPV Cation Channels; C459445:TRPV3 protein, human; D019700:Thrombospondin 1; D002118:Calcium