TY - JOUR
T1 - Hypoxia theranostics of a human prostate cancer xenograft and the resulting effects on the tumor microenvironment
AU - Krishnamachary, Balaji
AU - Mironchik, Yelena
AU - Jacob, Desmond
AU - Goggins, Eibhlin
AU - Kakkad, Samata
AU - Ofori, Francis
AU - Dore-Savard, Louis
AU - Bharti, Santosh Kumar
AU - Wildes, Flonne
AU - Penet, Marie France
AU - Black, Margaret E.
AU - Bhujwalla, Zaver M.
N1 - Publisher Copyright:
© 2020 The Authors
PY - 2020/12
Y1 - 2020/12
N2 - Hypoxia is frequently observed in human prostate cancer, and is associated with chemoresistance, radioresistance, metastasis, and castrate-resistance. Our purpose in these studies was to perform hypoxia theranostics by combining in vivo hypoxia imaging and hypoxic cancer cell targeting in a human prostate cancer xenograft. This was achieved by engineering PC3 human prostate cancer cells to express luciferase as well as a prodrug enzyme, yeast cytosine deaminase, under control of hypoxic response elements (HREs). Cancer cells display an adaptive response to hypoxia through the activation of several genes mediated by the binding of hypoxia inducible factors (HIFs) to HRE in the promoter region of target gene that results in their increased transcription. HIFs promote key steps in tumorigenesis, including angiogenesis, metabolism, proliferation, metastasis, and differentiation. HRE-driven luciferase expression allowed us to detect hypoxia in vivo to time the administration of the nontoxic prodrug 5-fluorocytosine that was converted by yeast cytosine deaminase, expressed under HRE regulation, to the chemotherapy agent 5-fluorouracil to target hypoxic cells. Conversion of 5-fluorocytosine to 5-fluorouracil was detected in vivo by 19F magnetic resonance spectroscopy. Morphological and immunohistochemical staining and molecular analyses were performed to characterize tumor microenvironment changes in cancer-associated fibroblasts, cell viability, collagen 1 fiber patterns, and HIF-1α. These studies expand our understanding of the effects of eliminating hypoxic cancer cells on the tumor microenvironment and in reducing stromal cell populations such as cancer-associated fibroblasts.
AB - Hypoxia is frequently observed in human prostate cancer, and is associated with chemoresistance, radioresistance, metastasis, and castrate-resistance. Our purpose in these studies was to perform hypoxia theranostics by combining in vivo hypoxia imaging and hypoxic cancer cell targeting in a human prostate cancer xenograft. This was achieved by engineering PC3 human prostate cancer cells to express luciferase as well as a prodrug enzyme, yeast cytosine deaminase, under control of hypoxic response elements (HREs). Cancer cells display an adaptive response to hypoxia through the activation of several genes mediated by the binding of hypoxia inducible factors (HIFs) to HRE in the promoter region of target gene that results in their increased transcription. HIFs promote key steps in tumorigenesis, including angiogenesis, metabolism, proliferation, metastasis, and differentiation. HRE-driven luciferase expression allowed us to detect hypoxia in vivo to time the administration of the nontoxic prodrug 5-fluorocytosine that was converted by yeast cytosine deaminase, expressed under HRE regulation, to the chemotherapy agent 5-fluorouracil to target hypoxic cells. Conversion of 5-fluorocytosine to 5-fluorouracil was detected in vivo by 19F magnetic resonance spectroscopy. Morphological and immunohistochemical staining and molecular analyses were performed to characterize tumor microenvironment changes in cancer-associated fibroblasts, cell viability, collagen 1 fiber patterns, and HIF-1α. These studies expand our understanding of the effects of eliminating hypoxic cancer cells on the tumor microenvironment and in reducing stromal cell populations such as cancer-associated fibroblasts.
KW - Cancer-associated fibroblasts
KW - Collagen 1 fibers
KW - Hypoxia
KW - Imaging
KW - Prodrug enzyme
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85093700802&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85093700802&partnerID=8YFLogxK
U2 - 10.1016/j.neo.2020.10.001
DO - 10.1016/j.neo.2020.10.001
M3 - Article
C2 - 33142234
AN - SCOPUS:85093700802
SN - 1522-8002
VL - 22
SP - 679
EP - 688
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 12
ER -