Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth

Martinez-Outschoorn, UE; Lisanti, MP; Sotgia, F

Abstract

Fibroblasts are the most abundant “non-cancerous” cells in tumors. However, it remains largely
unknown how these cancer-associated fibroblasts (CAFs) promote tumor growth and metastasis, driving
chemotherapy resistance and poor clinical outcome. This review summarizes new findings on CAF
signaling pathways and their emerging metabolic phenotypes that promote tumor growth. Although it
is well established that altered cancer metabolism enhances tumor growth, little is known about the role
of fibroblast metabolism in tumor growth. New studies reveal that metabolic coupling occurs between
catabolic fibroblasts and anabolic cancer cells, in many types of human tumors, including breast, prostate,
and head & neck cancers, as well as lymphomas. These catabolic phenotypes observed in CAFs are secondary
to a ROS-induced metabolic stress response. Mechanistically, this occurs via HIF1-alpha and NF<font size="1">K</font>B
signaling, driving oxidative stress, autophagy, glycolysis and senescence in stromal fibroblasts. These
catabolic CAFs then create a nutrient-rich microenvironment, to metabolically support tumor growth,
via the local stromal generation of mitochondrial fuels (lactate, ketone bodies, fatty acids, glutamine,
and other amino acids). New biomarkers of this catabolic CAF phenotype (such as caveolin-1 (Cav-1) and
MCT4), which are reversible upon treatment with anti-oxidants, are strong predictors of poor clinical
outcome in various types of human cancers. How cancer cells metabolically reprogram fibroblasts can
also help us to understand the effects of cancer cells at an organismal level, explaining para-neoplastic
phenomena, such as cancer cachexia. In conclusion, cancer should be viewed more as a systemic disease,
that engages the host-organism in various forms of energy-transfer and metabolic co-operation, across
a whole-body “ecosystem”.

Citation

Martinez-Outschoorn, U., Lisanti, M., & Sotgia, F. (2014). Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Seminars in Cancer Biology, 25, 47-60. https://doi.org/10.1016/j.semcancer.2014.01.005

• Journal Article Type: Article
• Publication Date: Jan 28, 2014
• Deposit Date: Jul 5, 2016
• Journal: Seminars in Cancer Biology
• Print ISSN: 1044-579X
• Publisher: Elsevier
• Volume: 25
• Pages: 47-60
• DOI: https://doi.org/10.1016/j.semcancer.2014.01.005
• Publisher URL: http://dx.doi.org/10.1016/j.semcancer.2014.01.005
• Related Public URLs: http://www.journals.elsevier.com/seminars-in-cancer-biology/
• Additional Information: Funders : Funder not known