Journal
CELL CYCLE
Volume 9, Issue 17, Pages 3485-3505Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.9.17.12721
Keywords
caveolin-1; autophagy; mitophagy; the Warburg effect; tumor stroma; metabolomics; ADMA (asymmetric dimethyl arginine); 3-hydroxybutyrate (ketone bodies); miR-31; miR-34c
Categories
Funding
- NIH/NCI [R01-CA-080250, R01-CA-098779, R01-CA-120876, R01-AR-055660, R01-CA-70896, R01-CA-75503, R01-CA-86072, R01-CA-107382]
- Susan G. Komen Breast Cancer Foundation
- Breast Cancer Alliance (BCA)
- American Cancer Society (ACS)
- W.W. Smith Charitable Trust
- Dr. Ralph and Marian C. Falk Medical Research Trust
- NIH/NCI Cancer Center [P30-CA-56036]
- Margaret Q. Landenberger Research Foundation
- Pennsylvania Department of Health
- Breakthrough Breast Cancer in the UK
- European Research Council
Ask authors/readers for more resources
A loss of stromal caveolin-1 (Cav-1) in the tumor fibroblast compartment is associated with early tumor recurrence, lymphnode metastasis and tamoxifen-resistance, resulting in poor clinical outcome in breast cancer patients. Here, we have used Cav-1 (-/-) null mice as a pre-clinical model for this lethal tumor micro-environment. Metabolic profiling of Cav-1 (-/-) mammary fat pads revealed the upregulation of numerous metabolites (nearly 100), indicative of a major catabolic phenotype. Our results are consistent with the induction of oxidative stress, mitochondrial dysfunction and autophagy/mitophagy. The two most prominent metabolites that emerged from this analysis were ADMA (asymmetric dimethyl arginine) and BHB (beta-hydroxybutyrate; a ketone body), which are markers of oxidative stress and mitochondrial dysfunction, respectively. Transcriptional profiling of Cav-1 (-/-) stromal cells and human tumor stroma from breast cancer patients directly supported an association with oxidative stress, mitochondrial dysfunction and autophagy/mitophagy, as well as ADMA and ketone production. MircoRNA profiling of Cav-1 (-/-) stromal cells revealed the upregulation of two key cancer-related miR's, namely miR-31 and miR-34c. Consistent with our metabolic findings, these miR's are associated with oxidative stress (miR-34c) or activation of the hypoxic response/HIF1a (miR-31), which is sufficient to drive authophagy/mitophagy. Thus, via an unbiased comprehensive analysis of a lethal tumor micro-environment, we have identified a number of candidate biomarkers (ADMA, ketones and miR-31/34c) that could be used to identify high-risk cancer patients at diagnosis, for treatment stratification and/or for evaluating therapeutic efficacy during anti-cancer therapy. We propose that the levels of these key biomarkers (ADMA, ketones/BHB, miR-31 and miR-34c) could be (i) assayed using serum or plasma from cancer patients or (ii) performed directly on excised tumor tissue. Importantly, induction of oxidative stress and autophagy/mitophagy in the tumor stromal compartment provides a means by which epithelial cancer cells can directly feed off of stromal-derived essential nutrients, chemical building blocks (amino acids, nucleotides) and energy-rich metabolites (glutamine, pyruvate, ketones/BHB), driving tumor progression and metastasis. Essentially, aggressive cancer cells are eating the cancer-associated fibroblasts via autophagy/mitophagy in the tumor micro-environment. Lastly, we discuss that this Autophagic Tumor Stroma Model of Cancer Metabolism provides a viable solution to the Autophagy Paradox in cancer etiology and chemo-therapy.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available