Skip to main content
NCBI home page
Medline Book to support NIHPA logoLink to Medline Book to support NIHPA
. 2021;1311:189–204. doi: 10.1007/978-3-030-65768-0_14

Metabolic Relationship Between Cancer-Associated Fibroblasts and Cancer Cells.

Christos Sazeides, Anne Le
PMCID: PMC9703248  PMID: 34014544

Abstract

Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME), play an important role in cancer initiation, progression, and metastasis. Recent findings have demonstrated that the TME not only provides physical support for cancer cells but also directs cell-to-cell interactions (in this case, the interaction between cancer cells and CAFs). As cancer progresses, the CAFs also coevolve, transitioning from an inactivated state to an activated state. The elucidation and understanding of the interaction between cancer cells and CAFs will pave the way for new cancer therapies [1-3].

Full text of this article can be found in Bookshelf.

References

  1. Zhao, X., He, Y., & Chen, H. (2013). Autophagic tumor stroma: Mechanisms and roles in tumor growth and progression. International Journal of Cancer, 132(1), 1–8. doi: 10.1002/ijc.27664. [DOI] [PubMed]
  2. Martinez-Outschoorn, U. E., et al. (2010). Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle, 9(16), 3256–3276. doi: 10.4161/cc.9.16.12553. [DOI] [PMC free article] [PubMed]
  3. Gascard, P., & Tlsty, T. D. (2016). Carcinoma-associated fibroblasts: Orchestrating the composition of malignancy. Genes & Development, 30(9), 1002–1019. doi: 10.1101/gad.279737.116. [DOI] [PMC free article] [PubMed]
  4. Spill, F., et al. (2016). Impact of the physical microenvironment on tumor progression and metastasis. Current Opinion in Biotechnology, 40, 41–48. doi: 10.1016/j.copbio.2016.02.007. [DOI] [PMC free article] [PubMed]
  5. Chen, Z., et al. (1999). Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clinical Cancer Research, 5(6), 1369–1379. [PubMed]
  6. Sriram, G., Bigliardi, P. L., & Bigliardi-Qi, M. (2015). Fibroblast heterogeneity and its implications for engineering organotypic skin models in vitro. European Journal of Cell Biology, 94(11), 483–512. doi: 10.1016/j.ejcb.2015.08.001. [DOI] [PubMed]
  7. Shimoda, M., Mellody, K. T., & Orimo, A. (2010). Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Seminars in Cell & Developmental Biology, 21(1), 19–25. doi: 10.1016/j.semcdb.2009.10.002. [DOI] [PMC free article] [PubMed]
  8. Rasanen, K., & Vaheri, A. (2010). Activation of fibroblasts in cancer stroma. Experimental Cell Research, 316(17), 2713–2722. doi: 10.1016/j.yexcr.2010.04.032. [DOI] [PubMed]
  9. Xouri, G., & Christian, S. (2010). Origin and function of tumor stroma fibroblasts. Seminars in Cell & Developmental Biology, 21(1), 40–46. doi: 10.1016/j.semcdb.2009.11.017. [DOI] [PubMed]
  10. Antonio, M. J., Zhang, C., & Le, A. (2021). Different tumor microenvironments lead to different metabolic phenotypes. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_10. doi: 10.1007/978-3-030-65768-0_10. [DOI] [PMC free article] [PubMed]
  11. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70. doi: 10.1016/s0092-8674(00)81683-9. [DOI] [PubMed]
  12. Pavlides, S., et al. (2010). Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect”: A transcriptional informatics analysis with validation. Cell Cycle, 9(11), 2201–2219. doi: 10.4161/cc.9.11.11848. [DOI] [PubMed]
  13. Hu, Y., et al. (2015). Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer. PLoS One, 10(5), e0125625. doi: 10.1371/journal.pone.0125625. [DOI] [PMC free article] [PubMed]
  14. DeFilippis, R. A., et al. (2014). Stress signaling from human mammary epithelial cells contributes to phenotypes of mammographic density. Cancer Research, 74(18), 5032–5044. doi: 10.1158/0008-5472.CAN-13-3390. [DOI] [PMC free article] [PubMed]
  15. Pietras, K., & Ostman, A. (2010). Hallmarks of cancer: Interactions with the tumor stroma. Experimental Cell Research, 316(8), 1324–1331. doi: 10.1016/j.yexcr.2010.02.045. [DOI] [PubMed]
  16. Semenza, G. L. (2008). Tumor metabolism: Cancer cells give and take lactate. The Journal of Clinical Investigation, 118(12), 3835–3837. doi: 10.1172/JCI37373. [DOI] [PMC free article] [PubMed]
  17. Pavlides, S., et al. (2009). The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle, 8(23), 3984–4001. doi: 10.4161/cc.8.23.10238. [DOI] [PubMed]
  18. Bose, S., Zhang, C., & Le, A. (2021). Glucose metabolism in cancer: The Warburg effect and beyond. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_1. doi: 10.1007/978-3-030-65768-0_1. [DOI] [PMC free article] [PubMed]
  19. Warburg, O., Wind, F., & Negelein, E. (1927). The metabolism of tumors in the body. The Journal of General Physiology, 8(6), 519–530. doi: 10.1085/jgp.8.6.519. [DOI] [PMC free article] [PubMed]
  20. Crabtree, H. G. (1929). Observations on the carbohydrate metabolism of tumours. The Biochemical Journal, 23(3), 536–545. doi: 10.1042/bj0230536. [DOI] [PMC free article] [PubMed]
  21. Feron, O. (2009). Pyruvate into lactate and back: From the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiotherapy and Oncology, 92(3), 329–333. doi: 10.1016/j.radonc.2009.06.025. [DOI] [PubMed]
  22. Christofk, H. R., et al. (2008). The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature, 452(7184), 230–233. doi: 10.1038/nature06734. [DOI] [PubMed]
  23. Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science, 324(5930), 1029–1033. doi: 10.1126/science.1160809. [DOI] [PMC free article] [PubMed]
  24. Shan, T., et al. (2017). Cancer-associated fibroblasts enhance pancreatic cancer cell invasion by remodeling the metabolic conversion mechanism. Oncology Reports, 37(4), 1971–1979. doi: 10.3892/or.2017.5479. [DOI] [PMC free article] [PubMed]
  25. Tape, C. J., et al. (2016). Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell, 165(4), 910–920. doi: 10.1016/j.cell.2016.03.029. [DOI] [PMC free article] [PubMed]
  26. Chiche, J., Brahimi-Horn, M. C., & Pouyssegur, J. (2010). Tumour hypoxia induces a metabolic shift causing acidosis: A common feature in cancer. Journal of Cellular and Molecular Medicine, 14(4), 771–794. doi: 10.1111/j.1582-4934.2009.00994.x. [DOI] [PMC free article] [PubMed]
  27. Swietach, P., et al. (2010). New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene, 29(50), 6509–6521. doi: 10.1038/onc.2010.455. [DOI] [PubMed]
  28. Gerlinger, M., et al. (2012). Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target. The Journal of Pathology, 227(2), 146–156. doi: 10.1002/path.4006. [DOI] [PMC free article] [PubMed]
  29. Martinez-Outschoorn, U. E., et al. (2010). Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle, 9(17), 3515–3533. doi: 10.4161/cc.9.17.12928. [DOI] [PMC free article] [PubMed]
  30. Lohr, M., et al. (2001). Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Research, 61(2), 550–555. [PubMed]
  31. Guido, C., et al. (2012). Metabolic reprogramming of cancer-associated fibroblasts by TGF-beta drives tumor growth: Connecting TGF-beta signaling with “Warburg-like” cancer metabolism and L-lactate production. Cell Cycle, 11(16), 3019–3035. doi: 10.4161/cc.21384. [DOI] [PMC free article] [PubMed]
  32. Pan, Y., et al. (2007). Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Molecular and Cellular Biology, 27(3), 912–925. doi: 10.1128/MCB.01223-06. [DOI] [PMC free article] [PubMed]
  33. Chandel, N. S., et al. (2000). Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: A mechanism of O2 sensing. The Journal of Biological Chemistry, 275(33), 25130–25138. doi: 10.1074/jbc.M001914200. [DOI] [PubMed]
  34. Salceda, S., & Caro, J. (1997). Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. The Journal of Biological Chemistry, 272(36), 22642–22647. doi: 10.1074/jbc.272.36.22642. [DOI] [PubMed]
  35. Bellot, G., et al. (2009). Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Molecular and Cellular Biology, 29(10), 2570–2581. doi: 10.1128/MCB.00166-09. [DOI] [PMC free article] [PubMed]
  36. Klimova, T., & Chandel, N. S. (2008). Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death and Differentiation, 15(4), 660–666. doi: 10.1038/sj.cdd.4402307. [DOI] [PubMed]
  37. Capparelli, C., et al. (2012). Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle, 11(12), 2285–2302. doi: 10.4161/cc.20718. [DOI] [PMC free article] [PubMed]
  38. Mercurio, F., et al. (1997). IKK-1 and IKK-2: Cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science, 278(5339), 860–866. doi: 10.1126/science.278.5339.860. [DOI] [PubMed]
  39. Cummins, E. P., et al. (2006). Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proceedings of the National Academy of Sciences of the United States of America, 103(48), 18154–18159. doi: 10.1073/pnas.0602235103. [DOI] [PMC free article] [PubMed]
  40. Martinez-Outschoorn, U. E., et al. (2011). Cytokine production and inflammation drive autophagy in the tumor microenvironment: Role of stromal caveolin-1 as a key regulator. Cell Cycle, 10(11), 1784–1793. doi: 10.4161/cc.10.11.15674. [DOI] [PMC free article] [PubMed]
  41. Wu, S., & Sun, J. (2011). Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. Discovery Medicine, 11(59), 325–335. [PMC free article] [PubMed]
  42. Bonello, S., et al. (2007). Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(4), 755–761. doi: 10.1161/01.ATV.0000258979.92828.bc. [DOI] [PubMed]
  43. Garcia-Cardena, G., et al. (1997). Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. The Journal of Biological Chemistry, 272(41), 25437–25440. doi: 10.1074/jbc.272.41.25437. [DOI] [PubMed]
  44. Martinez-Outschoorn, U. E., et al. (2011). Energy transfer in “parasitic” cancer metabolism: Mitochondria are the powerhouse and Achilles’ heel of tumor cells. Cell Cycle, 10(24), 4208–4216. doi: 10.4161/cc.10.24.18487. [DOI] [PMC free article] [PubMed]
  45. Sotgia, F., et al. (2012). Caveolin-1 and cancer metabolism in the tumor microenvironment: Markers, models, and mechanisms. Annual Review of Pathology, 7, 423–467. doi: 10.1146/annurev-pathol-011811-120856. [DOI] [PubMed]
  46. Martinez-Outschoorn, U. E., Sotgia, F., & Lisanti, M. P. (2012). Power surge: Supporting cells “fuel” cancer cell mitochondria. Cell Metabolism, 15(1), 4–5. doi: 10.1016/j.cmet.2011.12.011. [DOI] [PubMed]
  47. Pang, W., et al. (2015). Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts. Cancer Science, 106(10), 1362–1369. doi: 10.1111/cas.12747. [DOI] [PMC free article] [PubMed]
  48. Zhang, D., et al. (2015). Metabolic reprogramming of cancer-associated fibroblasts by IDH3alpha downregulation. Cell Reports, 10(8), 1335–1348. doi: 10.1016/j.celrep.2015.02.006. [DOI] [PubMed]
  49. Chen, S., et al. (2018). MiR-21-mediated metabolic alteration of cancer-associated fibroblasts and its effect on pancreatic cancer cell behavior. International Journal of Biological Sciences, 14(1), 100–110. doi: 10.7150/ijbs.22555. [DOI] [PMC free article] [PubMed] [Retracted]
  50. Gironella, M., et al. (2007). Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proceedings of the National Academy of Sciences of the United States of America, 104(41), 16170–16175. doi: 10.1073/pnas.0703942104. [DOI] [PMC free article] [PubMed]
  51. Saadi, H., Seillier, M., & Carrier, A. (2015). The stress protein TP53INP1 plays a tumor suppressive role by regulating metabolic homeostasis. Biochimie, 118, 44–50. doi: 10.1016/j.biochi.2015.07.024. [DOI] [PubMed]
  52. Selak, M. A., et al. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell, 7(1), 77–85. doi: 10.1016/j.ccr.2004.11.022. [DOI] [PubMed]
  53. Hoang, G., Udupa, S., & Le, A. (2019). Application of metabolomics technologies toward cancer prognosis and therapy. International Review of Cell and Molecular Biology, 347, 191–223. doi: 10.1016/bs.ircmb.2019.07.003. [DOI] [PubMed]
  54. Zhao, H., et al. (2016). Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife, 5, e10250. doi: 10.7554/eLife.10250. [DOI] [PMC free article] [PubMed]
  55. Dang, C. V. (2010). Glutaminolysis: Supplying carbon or nitrogen or both for cancer cells? Cell Cycle, 9(19), 3884–3886. doi: 10.4161/cc.9.19.13302. [DOI] [PubMed]
  56. Daye, D., & Wellen, K. E. (2012). Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis. Seminars in Cell & Developmental Biology, 23(4), 362–369. doi: 10.1016/j.semcdb.2012.02.002. [DOI] [PubMed]
  57. Li, T., Copeland, C., & Le, A. (2021). Glutamine metabolism in cancer. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_2. doi: 10.1007/978-3-030-65768-0_2. [DOI] [PMC free article] [PubMed]
  58. Le, A., et al. (2012). Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metabolism, 15(1), 110–121. doi: 10.1016/j.cmet.2011.12.009. [DOI] [PMC free article] [PubMed]
  59. Metallo, C. M., et al. (2011). Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature, 481(7381), 380–384. doi: 10.1038/nature10602. [DOI] [PMC free article] [PubMed]
  60. Kamphorst, J. J., et al. (2014). Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer & Metabolism, 2, 23. doi: 10.1186/2049-3002-2-23. [DOI] [PMC free article] [PubMed]
  61. Kumar-Sinha, C., et al. (2003). Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. Cancer Research, 63(1), 132–139. [PubMed]
  62. Guarente, L. (2013). Calorie restriction and sirtuins revisited. Genes & Development, 27(19), 2072–2085. doi: 10.1101/gad.227439.113. [DOI] [PMC free article] [PubMed]
  63. Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012). Sirtuins as regulators of metabolism and healthspan. Nature Reviews. Molecular Cell Biology, 13(4), 225–238. doi: 10.1038/nrm3293. [DOI] [PMC free article] [PubMed]
  64. Gambini, J., et al. (2011). Free [NADH]/[NAD(+)] regulates sirtuin expression. Archives of Biochemistry and Biophysics, 512(1), 24–29. doi: 10.1016/j.abb.2011.04.020. [DOI] [PubMed]
  65. Nemoto, S., Fergusson, M. M., & Finkel, T. (2005). SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. The Journal of Biological Chemistry, 280(16), 16456–16460. doi: 10.1074/jbc.M501485200. [DOI] [PubMed]
  66. Benton, C. R., et al. (2008). PGC-1alpha increases skeletal muscle lactate uptake by increasing the expression of MCT1 but not MCT2 or MCT4. Physiological Genomics, 35(1), 45–54. doi: 10.1152/physiolgenomics.90217.2008. [DOI] [PubMed]
  67. Rodgers, J. T., et al. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 434(7029), 113–118. doi: 10.1038/nature03354. [DOI] [PubMed]
  68. Tan, Z., et al. (2016). The role of PGC1alpha in cancer metabolism and its therapeutic implications. Molecular Cancer Therapeutics, 15(5), 774–782. doi: 10.1158/1535-7163.MCT-15-0621. [DOI] [PubMed]
  69. Ippolito, L., et al. (2019). Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer. Oncogene, 38(27), 5339–5355. doi: 10.1038/s41388-019-0805-7. [DOI] [PubMed]
  70. Sousa, C. M., et al. (2016). Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature, 536(7617), 479–483. doi: 10.1038/nature19084. [DOI] [PMC free article] [PubMed]
  71. Marino, G., & Kroemer, G. (2010). Ammonia: A diffusible factor released by proliferating cells that induces autophagy. Science Signaling, 3(124), pe19. doi: 10.1126/scisignal.3124pe19. [DOI] [PubMed]
  72. Eng, C. H., & Abraham, R. T. (2010). Glutaminolysis yields a metabolic by-product that stimulates autophagy. Autophagy, 6(7), 968–970. doi: 10.4161/auto.6.7.13082. [DOI] [PMC free article] [PubMed]
  73. Gong, J., et al. (2020). Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells. Cell Death & Disease, 11(4), 267. doi: 10.1038/s41419-020-2434-z. [DOI] [PMC free article] [PubMed]
  74. Park, J. K., et al. (2021). The heterogeneity of lipid metabolism in cancer. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_3. doi: 10.1007/978-3-030-65768-0_3. [DOI] [PMC free article] [PubMed]
  75. Nabi, K., & Le, A. (2021). The intratumoral heterogeneity of cancer metabolism. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_11. doi: 10.1007/978-3-030-65768-0_11. [DOI] [PMC free article] [PubMed]
  76. Jung, J. G., & Le, A. (2021). Targeting metabolic cross talk between cancer cells and cancer-associated fibroblasts. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_15 doi: 10.1007/978-3-030-65768-0_15. [DOI] [PMC free article] [PubMed]

RESOURCES