Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling
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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.
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mTOR kinase has a master regulatory role in developing therapy resistance.
“This finding calls the attention to the master regulatory role of mTOR kinase in developing therapy resistance [98].”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [98]
The activity pattern of mTOR shows intratumoral heterogeneity as a consequence of anti-angiogenic therapies.
“It was observed that the activity pattern of mTOR shows intratumoral heterogeneity as a consequence of anti-angiogenic therapies.”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [98]
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- Authors
- Allen, E., Miéville, P., Warren, C. M., Saghafinia, S., Li, L., Peng, M.-W., & Hanahan, D.
- Affiliations
- ISREC Foundation (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University of California, Los Angeles (US)
- Swiss Cancer Center Léman (CH)
- Corresponding author
- Hanahan, Douglas
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 15
- Issue
- 6
- Pages
- 1144-1160
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4872464
- OpenAlex
- W2342466981
- Cited by
- 221
- References
- 51
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 13 · 2023: 15 · 2022: 20 · 2021: 26 · 2020: 32 · 2019: 17 · 2018: 27 · 2017: 33 · 2016: 12
- FWCI
- 12.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- metabolic symbiosis, anti-angiogenic therapy resistance, VEGF inhibitors, mTOR signaling, tumor hypoxia, lactate transport, GLUT1, MCT4, MCT1, GLUT2, glutamine metabolism, glycolysis, HIF-1α, tumor microenvironment, cancer metabolism
- MeSH terms
- Sunitinib, Axitinib, Animals, Glucose, Glutamine, Glycolysis, Humans, Imidazoles, Indazoles, Indoles, Intestinal Neoplasms, Models, Biological, Pancreatic Neoplasms, Pyrroles, Stomach Neoplasms, Signal Transduction, Up-Regulation, Gene Expression Regulation, Neoplastic, Neuroendocrine Tumors, Drug Resistance, Neoplasm, Lactic Acid, Sirolimus, Angiogenesis Inhibitors, Membrane Transport Proteins, Cell Line, Tumor, Mice, TOR Serine-Threonine Kinases
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