Noninvasive multiparametric imaging of metastasis-permissive microenvironments in a human prostate cancer xenograft.
Metastasis continues to be one of the major causes of mortality from prostate cancer. Because human malignant cell lines metastasize more readily from orthotopic sites than from heterotopic sites, to identify metastasis-permissive tumor microenvironments, we used noninvasive imaging to compare the in vivo vascular, metabolic, and physiologic characteristics of a human prostate cancer xenograft implanted orthotopically in the prostate or s.c. in the flank. Hypoxia was detected in these xenografts by placing an enhanced green fluorescence protein optical reporter under the control of a hypoxia response element. A multiparametric analysis of hypoxia, extracellular pH, vascularization, and metabolism provided a characterization of environments that are permissive for metastasis to occur. We found that orthotopic tumors, which metastasized more easily, were characterized by higher vascular volume, permeability, and total choline and a more acidic extracellular pH. Interestingly, metastatic deposits in the lymph nodes as well as cancer cells in ascites fluid were found to be hypoxic, explaining, in part, the refractory nature of metastatic disease. These results also provide the basis for clinically translatable noninvasive imaging markers for predicting metastatic risk in prostate cancer.
The Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University In Vivo Cellular and Molecular Imaging Center Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Marie-France
MF
Penet
Arvind P
AP
Pathak
Venu
V
Raman
Paloma
P
Ballesteros
Dmitri
D
Artemov
Zaver M
ZM
Bhujwalla
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging / Q000379:methods; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000503:physiopathology*; D014183:Transplantation, Heterologous