title: Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling.
abstract: Therapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1α-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2.
authors.affiliation: The Swiss Institute for Experimental Cancer Research (ISREC), EPFL SV ISREC, Station 19, 1015 Lausanne, Switzerland.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Allen
authors.affiliation: The Institute of Chemical Sciences and Engineering (ISIC-SB-EPFL), Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC-Direction, CH A3 398 Station 6, 1015 Lausanne, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Miéville
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Warren
authors.affiliation: The Swiss Institute for Experimental Cancer Research (ISREC), EPFL SV ISREC, Station 19, 1015 Lausanne, Switzerland.
authors.forename: Sadegh
authors.initials: S
authors.lastname: Saghafinia
authors.affiliation: The Swiss Institute for Experimental Cancer Research (ISREC), EPFL SV ISREC, Station 19, 1015 Lausanne, Switzerland.
authors.forename: Leanne
authors.initials: L
authors.lastname: Li
authors.affiliation: The Swiss Institute for Experimental Cancer Research (ISREC), EPFL SV ISREC, Station 19, 1015 Lausanne, Switzerland.
authors.forename: Mei-Wen
authors.initials: MW
authors.lastname: Peng
authors.affiliation: The Swiss Institute for Experimental Cancer Research (ISREC), EPFL SV ISREC, Station 19, 1015 Lausanne, Switzerland; The Swiss Cancer Center Lausanne (SCCL), Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: dh@epfl.ch.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000077784:Axitinib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007414:Intestinal Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018358:Neuroendocrine Tumors / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism*; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D026901:Membrane Transport Proteins; D011758:Pyrroles; D005973:Glutamine; D019344:Lactic Acid; D000077784:Axitinib; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D000077210:Sunitinib; D020123:Sirolimus