title: Defining Cancer Subpopulations by Adaptive Strategies Rather Than Molecular Properties Provides Novel Insights into Intratumoral Evolution.
abstract: Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern the underlying Darwinian dynamics. In three spontaneous murine cancers (prostate cancers in TRAMP and PTEN mice, pancreatic cancer in KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies that remained stable in culture: (i) invasive cells that produce an acidic environment via upregulated aerobic glycolysis; and (ii) noninvasive cells that were angiogenic and metabolically near-normal. Darwinian interactions of these subpopulations were investigated in TRAMP prostate cancers. Computer simulations demonstrated invasive, acid-producing (C2) cells maintain a fitness advantage over noninvasive, angiogenic (C3) cells by promoting invasion and reducing efficacy of immune response. Immunohistochemical analysis of untreated tumors confirmed that C2 cells were invariably more abundant than C3 cells. However, the C2 adaptive strategy phenotype incurred a significant cost due to inefficient energy production (i.e., aerobic glycolysis) and depletion of resources for adaptations to an acidic environment. Mathematical model simulations predicted that small perturbations of the microenvironmental extracellular pH (pHe) could invert the cost/benefit ratio of the C2 strategy and select for C3 cells.In vivo, 200 mmol/L NaHCO3added to the drinking water of 4-week-old TRAMP mice increased the intraprostatic pHe by 0.2 units and promoted proliferation of noninvasive C3 cells, which remained confined within the ducts so that primary cancer did not develop. A 0.2 pHe increase in established tumors increased the fraction of C3 cells and signficantly diminished growth of primary and metastatic tumors. In an experimental tumor construct, MCF7 and MDA-MB-231 breast cancer cells were coinjected into the mammary fat pad of SCID mice. C2-like MDA-MB-231 cells dominated in untreated animals, but C3-like MCF7 cells were selected and tumor growth slowed when intratumoral pHe was increased. Overall, our data support the use of mathematical modeling of intratumoral Darwinian interactions of environmental selection forces and cancer cell adaptive strategies. These models allow the tumor to be steered into a less invasive pathway through the application of small but selective biological force.Cancer Res; 77(9); 2242-54. ©2017 AACR.
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Arig
authors.initials: A
authors.lastname: Ibrahim-Hashim
authors.affiliation: Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Mark
authors.initials: M
authors.lastname: Robertson-Tessi
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Enriquez-Navas
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Damaghi
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Yoganand
authors.initials: Y
authors.lastname: Balagurunathan
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Wojtkowiak
authors.affiliation: Department of Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida.
authors.forename: Shonagh
authors.initials: S
authors.lastname: Russell
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Kam
authors.initials: K
authors.lastname: Yoonseok
authors.affiliation: Analytic Microscopy Core, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Lloyd
authors.affiliation: Analytic Microscopy Core, H. Lee Moffitt Cancer Center, Tampa, Florida.|Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Marilyn M
authors.initials: MM
authors.lastname: Bui
authors.affiliation: Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida.|Department of Evolutionary Biology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Brown
authors.affiliation: Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Alexander R A
authors.initials: ARA
authors.lastname: Anderson
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida.|Department of Radiology, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
authors.affiliation: Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida. robert.gatenby@moffitt.org.|Department of Radiology, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Gatenby
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D003198:Computer Simulation; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008962:Models, Theoretical; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics*; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse