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The adipocyte microenvironment and cancer

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Abstract

Many epithelial tumors grow in the vicinity of or metastasize to adipose tissue. As tumors develop, crosstalk between adipose tissue and cancer cells leads to changes in adipocyte function and paracrine signaling, promoting a microenvironment that supports tumor growth. Over the last decade, it became clear that tumor cells co-opt adipocytes in the tumor microenvironment, converting them into cancer-associated adipocytes (CAA). As adipocytes and cancer cells engage, a metabolic symbiosis ensues that is driven by bi-directional signaling. Many cancers (colon, breast, prostate, lung, ovarian cancer, and hematologic malignancies) stimulate lipolysis in adipocytes, followed by the uptake of fatty acids (FA) from the surrounding adipose tissue. The FA enters the cancer cell through specific fatty acid receptors and binding proteins (e.g., CD36, FATP1) and are used for membrane synthesis, energy metabolism (β-oxidation), or lipid-derived cell signaling molecules (derivatives of arachidonic and linolenic acid). Therefore, blocking adipocyte-derived lipid uptake or lipid-associated metabolic pathways in cancer cells, either with a single agent or in combination with standard of care chemotherapy, might prove to be an effective strategy against cancers that grow in lipid-rich tumor microenvironments.

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Abbreviations

ATP:

Adenosine triphosphate

BAT:

Brown adipose tissue

CAA:

Cancer-associated adipocytes

CPT1:

Carnitine palmitoyltransferase 1A

EMT:

Epithelial-mesenchymal transition

FA:

Fatty acids

FABP:

Fatty acid-binding protein

FAT:

Fatty acid translocase

FATP:

Fatty acid transport protein

FAO:

Fatty acid oxidation

Gatm:

Glycine amidinotransferase

HFD:

High-fat diet

MMe:

Metabolically activated macrophages

Mox:

Redox-regulatory macrophages

MAGL:

Monoacylglycerol lipase

miRNA:

MicroRNA

NK:

Natural killer

PDX:

Patient-derived xenograft

PUFA:

Polyunsaturated fatty acids

SAT:

Subcutaneous adipose tissue

SLC27A1:

Solute carrier family 27 member 1

SVF:

Stromal vascular fraction

TAM:

Tumor-associated macrophages

TME:

Tumor microenvironment

Tregs:

T regulatory cells

UCP1:

Uncoupling protein 1

VAT:

Visceral adipose tissue

WAT:

White adipose tissue

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Funding

This study is funded by DOD pilot award (W81XWH2110376) to Abir Mukherjee (A.M) and NIH grant (R01CA169604, R35CA264619) awarded to Ernst Lengyel (E.L). We thank Gail Isenberg for editing the manuscript. Illustrations were generated using biorender.com.

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Correspondence to Ernst Lengyel.

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E. L. receives research funding for preclinical ovarian cancer studies from Abbvie and Arsenal Bioscience outside of the scope of this work and is co-inventor on a patent proposing to use FABP inhibitors for ovarian cancer treatment. A. M. and A. J. B. have no conflicts to report.

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Mukherjee, A., Bilecz, A.J. & Lengyel, E. The adipocyte microenvironment and cancer. Cancer Metastasis Rev 41, 575–587 (2022). https://doi.org/10.1007/s10555-022-10059-x

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