Drilling for Oil: Tumor-Surrounding Adipocytes Fueling Cancer

doi:10.1016/j.trecan.2020.03.001

Trends in Cancer

Volume 6, Issue 7, July 2020, Pages 593-604

https://doi.org/10.1016/j.trecan.2020.03.001 Get rights and content

Highlights

Cancer cells activate lipolysis in tumor-surrounding adipocytes leading to the release of FFAs
The release of lipids also occurs through extracellular vesicles secreted by adipocytes.
The tumor-derived signals that force adipocytes to deliver lipids are not fully described.
Lipids are taken up by cancer cells and mainly stored as neutral lipids in lipid droplets.
Cancer cells possess the ability to liberate FFAs from these stores using neutral or acid lipases.
FFAs are used by cancer cells to promote tumor progression mainly through mitochondrial fatty acid oxidation that could be coupled or not to ATP production.
Other mechanisms independent of mitochondrial activity have also been implicated in tumor progression.
Due to defective lipolysis of bone marrow adipocytes, this metabolic symbiosis, if it exists in bone marrow, would involve different mechanisms.

Over the past decade, it has become apparent that metabolic reprogramming is a key event in tumor progression. The tumor microenvironment (TME) is a source of metabolites for tumor cells. Lipid-filled mature adipocytes are frequently found in proximity to invasive human tumors and release free fatty acids (FFAs) through lipolysis. These FFAs are taken up by tumor cells and used to promote tumor progression by mechanisms that include mitochondrial fatty acid oxidation (FAO). This review discusses recent advances in our understanding of this metabolic symbiosis between adipocytes and cancer cells and underlines the differences in this metabolic crosstalk between the various types of cancer and their localization.

Section snippets

TME: A Source of Metabolites for Cancer Cells

Metabolic reprograming is a hallmark of cancer, as defined in 2011 by Hanahan and Weinberg [1] and is an active research field in the development of new anticancer drugs. The metabolic phenotype of cancer cells depends on intrinsic factors such as genetic alterations, specificities of tissue origin, and tumor state, but also on extrinsic factors that comprise interactions with the TME [2]. The metabolic flexibility of cancer cells allows them to use different metabolites to produce energy,

Adipocytes Are a Major Component of the TME

Mature adipocytes are one of the main components of many TMEs. WAT is found in close proximity to invasive cancers such as breast [mammary adipose tissue (MAT)], prostate [periprostatic adipose tissue (PPAT)], colon [visceral adipose tissue (VAT)], and melanoma [subcutaneous adipose tissue (SAT)] and cancer cells come into contact with WAT on crossing the basement membrane. Adipocytes are also present in the TME of hematological malignancies such as acute myeloid leukemia (AML) and multiple

Transfer and Fate of Lipid in Tumor Cells: A Matter of Tumor Type?

We have seen that tumor-surrounding adipocytes are able to release FFAs [5,13., 14., 15.,48] or EV-contained FFAs [34]. We now describe how these lipids are transferred into tumor cells, their metabolic fate inside tumor cells, and how they promote tumor progression (Box 3).

Concluding Remarks

Adipocytes are major components of the TME in a large number of cancers and their role in tumor progression is increasingly recognized. Although growing evidence shows that cancer cells are likely to use this lipid reservoir to promote tumor progression, several questions remain unanswered (see Outstanding Questions). Most studies reported in this review use adipocytes obtained from preadipocyte cell lines or isolated adipose progenitors differentiated in vitro, useful as ‘first-step’ models to

Acknowledgments

The authors thank Charlotte Somes for English editing of the manuscript. Studies performed in our laboratory are supported by the Fondation de France, the Fondation ARC (Association pour la Recherche sur le Cancer), the Fondation Toulouse Cancer Santé, the Ligue Contre le Cancer, and the Société Française de Dermatologie.

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Deciphering the mechanisms behind how T cells become exhausted and regulatory T cells (Tregs) differentiate in a tumor microenvironment (TME) will significantly benefit cancer immunotherapy. A common metabolic alteration feature in TME is lipid accumulation, associated with T cell exhaustion and Treg differentiation. However, the regulatory role of free fatty acids (FFA) on T cell antitumor immunity has yet to be clearly illustrated. Our study observed that palmitic acid (PA), the most abundant saturated FFA in mouse plasma, enhanced T cell exhaustion and Tregs population in TME and increased tumor growth. In contrast, oleic acid (OA), a monounsaturated FFA, rescued PA-induced T cell exhaustion, decreased Treg population, and ameliorated T cell antitumor immunity in an obese mouse model. Mechanistically, mitochondrial metabolic activity is critical in maintaining T cell function, which PA attenuated. PA-induced T cell exhaustion and Treg formation depended on CD36 and Akt/mTOR-mediated calcium signaling. The study described a new mechanism of PA-induced downregulation of antitumor immunity of T cells and the therapeutic potential behind its restoration by targeting PA.
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Bidirectional interactions between cancer cells and their microenvironment govern tumor progression. Among the stromal cells in this microenvironment, adipocytes have been reported to upregulate cancer cell migration and invasion by producing fatty acids. Conversely, cancer cells alter adipocyte phenotype notably via increased lipolysis. We aimed to identify the mechanisms through which cancer cells trigger adipocyte lipolysis and evaluate the functional consequences on cancer progression. Here, we show that cancer cell-induced acidification of the extracellular medium strongly promotes preadipocyte lipolysis through a mechanism that does not involve lipophagy but requires adipose triglyceride lipase (ATGL) activity. This increased lipolysis is triggered mainly by attenuation of the G0/G1 switch gene 2 (G0S2)-induced inhibition of ATGL. G0S2-mediated regulation in preadipocytes affects their communication with breast cancer cells, modifying the phenotype of the cancer cells and increasing their resistance to chemotherapeutic agents in vitro. Furthermore, we demonstrate that the adipocyte-specific overexpression of G0S2 impairs mammary tumor growth and lung metastasis formation in vivo. Our results highlight the importance of acidosis in cancer cell-adipocyte crosstalk and identify G0S2 as the main regulator of cancer-induced lipolysis, regulating tumor establishment and spreading.
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In ovarian cancer, the omental metastatic tumors are characterized by extensive ECM deposition and remodelling. Both cancer and stromal cells promote a desmoplastic reaction that transforms the fatty omentum into a stiff, fibrotic tissue, coincident with cancer cell-mediated lipolysis of adipocytes to fuel tumor growth [200,201]. Of note, high ECM expression in omental tumors has been linked to an unfavourable immune landscape and poor patient survival [201].
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Fatty acids are transported across cell membrane actively by several transmembrane transporters, such as fatty acid translocase/CD36, fatty acid transport proteins. Also, some specialized small proteins like fatty acid binding proteins which bind free fatty acids (FFAs) and facilitate FFAs intracellular transport74. To satisfy the metabolic need of HCC cells, these fatty acid transportation machineries are increased significantly in malignant tissues compared with adjacent tissues and normal liver cells.
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Trends in Cancer

ReviewDrilling for Oil: Tumor-Surrounding Adipocytes Fueling Cancer

Highlights

Section snippets

TME: A Source of Metabolites for Cancer Cells

Adipocytes Are a Major Component of the TME

Transfer and Fate of Lipid in Tumor Cells: A Matter of Tumor Type?

Concluding Remarks

Acknowledgments

Cell

Dev. Cell

Trends Cancer

Trends Pharmacol. Sci.

Cell Metab.

Cell Stem Cell

Biochim. Biophys. Acta

Eur. J. Cancer

Blood

J. Lipid Res.

Biochim. Biophys. Acta

Am. J. Pathol.

Bone

Cell Rep.

J. Lipid Res.

J. Biol. Chem.

Cell Rep.

Mol. Cell. Endocrinol.

Chem. Biol.

Cell

Biochem. Biophys. Res. Commun.

Cell Metab.

Cell Rep.

Trends Biochem. Sci.

Cell Metab.

Biochim. Biophys. Acta

Semin. Cancer Biol.

Cell Metab.

Biochem. Biophys. Rep.

Trends Cell Biol.

Prog. Lipid Res.

Biochim. Biophys. Acta Bioenerg.

Cancer metabolism: a therapeutic perspective

Nat. Rev. Clin. Oncol.

Lipid metabolic reprogramming in cancer cells

Oncogenesis

Extracellular fatty acids are the major contributor to lipid synthesis in prostate cancer

Mol. Cancer Res.

Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration

Cancer Metab.

The fat and the bad: mature adipocytes, key actors in tumor progression and resistance

Oncotarget

Obesity and cancer – mechanisms underlying tumour progression and recurrence

Nat. Rev. Endocrinol.

Obesity and melanoma: could fat be fueling malignancy?

Pigment Cell Melanoma Res.

Microenvironmental regulation of tumor progression and metastasis

Nat. Med.

Periprostatic adipose tissue favors prostate cancer cell invasion in an obesity-dependent manner: role of oxidative stress

Mol. Cancer Res.

Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth

Nat. Med.

Review
Drilling for Oil: Tumor-Surrounding Adipocytes Fueling Cancer