TY - JOUR
T1 - All-human microphysical model of metastasis therapy
AU - Wheeler, Sarah E.
AU - Borenstein, Jeffrey T.
AU - Clark, Amanda M.
AU - Ebrahimkhani, Mohammed
AU - Fox, Ira J.
AU - Griffith, Linda
AU - Inman, Walker
AU - Lauffenburger, Douglas
AU - Nguyen, Transon
AU - Pillai, Venkateswaran C.
AU - Prantil-Baun, Rachelle
AU - Stolz, Donna B.
AU - Taylor, Donald
AU - Ulrich, Theresa
AU - Venkataramanan, Raman
AU - Wells, Alan
AU - Young, Carissa
N1 - Funding Information:
Funding for publication of this article came from grants NIH 1UH2TR000496-01 (All-human Microphysical Model of Metastasis Therapy) and DARPA-BAA-11-73 (Microphysiological Systems: W911NF-12-2-0039 Barrier-Immune-Organ: Microphysiology, Microenvironment Engineered Tissue Construct Systems (BIO-MIMETICS)).
PY - 2013/12/20
Y1 - 2013/12/20
N2 - The vast majority of cancer mortalities result from distant metastases. The metastatic microenvironment provides unique protection to ectopic tumors as the primary tumors often respond to specific agents. Although significant interventional progress has been made on primary tumors, the lack of relevant accessible model in vitro systems in which to study metastases has plagued metastatic therapeutic development - particularly among micrometastases. A real-time, all-human model of metastatic seeding and cancer cells that recapitulate metastatic growth and can be probed in real time by a variety of measures and challenges would provide a critical window into the pathophysiology of metastasis and pharmacology of metastatic tumor resistance. To achieve this we are advancing our microscale bioreactor that incorporates human hepatocytes, human nonparenchymal liver cells, and human breast cancer cells to mimic the hepatic niche in three dimensions with functional tissue. This bioreactor is instrumented with oxygen sensors, micropumps capable of generating diurnally varying profiles of nutrients and hormones, while enabling real-time sampling. Since the liver is a major metastatic site for a wide variety of carcinomas and other tumors, this bioreactor uniquely allows us to more accurately recreate the human metastatic microenvironment and probe the paracrine effects between the liver parenchyma and metastatic cells. Further, as the liver is the principal site of xenobiotic metabolism, this reactor will help us investigate the chemotherapeutic response within a metabolically challenged liver microenvironment. This model is anticipated to yield markers of metastatic behavior and pharmacologic metabolism that will enable better clinical monitoring, and will guide the design of clinical studies to understand drug efficacy and safety in cancer therapeutics. This highly instrumented bioreactor format, hosting a growing tumor within a microenvironment and monitoring its responses, is readily transferable to other organs, giving this work impact beyond the liver.
AB - The vast majority of cancer mortalities result from distant metastases. The metastatic microenvironment provides unique protection to ectopic tumors as the primary tumors often respond to specific agents. Although significant interventional progress has been made on primary tumors, the lack of relevant accessible model in vitro systems in which to study metastases has plagued metastatic therapeutic development - particularly among micrometastases. A real-time, all-human model of metastatic seeding and cancer cells that recapitulate metastatic growth and can be probed in real time by a variety of measures and challenges would provide a critical window into the pathophysiology of metastasis and pharmacology of metastatic tumor resistance. To achieve this we are advancing our microscale bioreactor that incorporates human hepatocytes, human nonparenchymal liver cells, and human breast cancer cells to mimic the hepatic niche in three dimensions with functional tissue. This bioreactor is instrumented with oxygen sensors, micropumps capable of generating diurnally varying profiles of nutrients and hormones, while enabling real-time sampling. Since the liver is a major metastatic site for a wide variety of carcinomas and other tumors, this bioreactor uniquely allows us to more accurately recreate the human metastatic microenvironment and probe the paracrine effects between the liver parenchyma and metastatic cells. Further, as the liver is the principal site of xenobiotic metabolism, this reactor will help us investigate the chemotherapeutic response within a metabolically challenged liver microenvironment. This model is anticipated to yield markers of metastatic behavior and pharmacologic metabolism that will enable better clinical monitoring, and will guide the design of clinical studies to understand drug efficacy and safety in cancer therapeutics. This highly instrumented bioreactor format, hosting a growing tumor within a microenvironment and monitoring its responses, is readily transferable to other organs, giving this work impact beyond the liver.
KW - liver
KW - mammary carcinoma
KW - microenvironment
KW - tumor dissemination
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U2 - 10.1186/scrt372
DO - 10.1186/scrt372
M3 - Review article
C2 - 24565274
AN - SCOPUS:84891358491
SN - 1757-6512
VL - 4
JO - Stem Cell Research and Therapy
JF - Stem Cell Research and Therapy
IS - SUPPL.1
M1 - S11
ER -