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Nutrient scavenging in cancer

Nature Reviews Cancer volume 18, pages 619–633 (2018)Cite this article

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Abstract

While cancer cell proliferation depends on access to extracellular nutrients, inadequate tumour perfusion means that glucose, amino acids and lipids are often in short supply. To overcome this obstacle to growth, cancer cells utilize multiple scavenging strategies, obtaining macromolecules from the microenvironment and breaking them down in the lysosome to produce substrates for ATP generation and anabolism. Recent studies have revealed four scavenging pathways that support cancer cell proliferation in low-nutrient environments: scavenging of extracellular matrix proteins via integrins, receptor-mediated albumin uptake and catabolism, macropinocytic consumption of multiple components of the tumour microenvironment and the engulfment and degradation of entire live cells via entosis. New evidence suggests that blocking these pathways alone or in combination could provide substantial benefits to patients with incurable solid tumours. Both US Food and Drug Administration (FDA)-approved drugs and several agents in preclinical or clinical development shut down individual or multiple scavenging pathways. These therapies may increase the extent and durability of tumour growth inhibition and/or prevent the development of resistance when used in combination with existing treatments. This Review summarizes the evidence suggesting that scavenging pathways drive tumour growth, highlights recent advances that define the oncogenic signal transduction pathways that regulate scavenging and considers the benefits and detriments of therapeutic strategies targeting scavenging that are currently under development.

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Fig. 1: Receptor-mediated scavenging of albumin and extracellular matrix proteins.
Fig. 2: Scavenging through macropinocytosis and entosis.
Fig. 3: Pathway specificity in nutrient scavenging.

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Acknowledgements

A.L.E. was supported by grants from the Congressionally Directed Medical Research Programs (CDMRP) (W81XWH-15-1-0010), the University of California Cancer Research Coordinating Committee (CRR-17-426826), University of California Irvine (UCI) Applied Innovation and the UCI Chao Family Comprehensive Cancer Center Anti-Cancer Challenge. The authors thank the referees for the peer review of this work.

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Nature Reviews Cancer thanks J. Swanson, A. Thorburn and the anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA

    Brendan T. Finicle, Vaishali Jayashankar & Aimee L. Edinger

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All authors contributed to substantial discussions, research and collection of references and the writing and editing of the article. B.T.F. and A.L.E. organized and planned the display figures and boxes.

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Correspondence to Aimee L. Edinger.

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A.L.E. is listed as an inventor on a patent covering the synthesis of SH-BC-893 and its use as a treatment for cancer and other diseases.

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Glossary

Desmoplasia

A process by which dense stromal cells extensively deposit extracellular matrix proteins, increasing interstitial pressure and decreasing vascular perfusion.

Anabolism

The biosynthetic processes that assembles nutrients into macromolecules that contribute to cellular biomass.

Nutrient scavenging

The removal and breakdown of macromolecules from the microenvironment into components that can be used for ATP production and/or anabolism.

Recycling

The catabolism of a cell’s own macromolecules into subunits that are used to fuel ATP production or to synthesize new polymers; autophagy is a recycling process.

Cell-autonomous growth

Cellular growth (both biosynthesis and proliferation) that does not depend on building blocks produced by other cells.

Collagen

The most abundant structural protein in the ECM.

Laminin

A high molecular weight heterotrimeric glycoprotein that forms the basement membrane that facilitates cell adhesion and tissue structural maintenance.

Fibronectin

A high-molecular-mass protein dimer that binds cell membrane integrin receptors and neighbouring extracellular matrix proteins like collagen to facilitate cell adhesion.

Integrins

Heterodimeric receptors that facilitate cell adhesion to extracellular matrix (ECM) and coordinate diverse signalling processes. Internalization of integrins allows scavenging of ECM components.

Anoikis

A form of programmed cell death induced by detachment of anchorage-dependent cells from the extracellular matrix; metastatic tumour cells escape death by anoikis and become anchorage-independent.

Albumin

The most abundant serum protein; albumin facilitates transport of solutes (fatty acids, vitamins, metal ions, and so on) throughout the body.

Macropinocytosis

A non-selective form of endocytosis by which cells assimilate both extracellular fluid and macromolecules by generating large, uncoated endocytic vesicles (macropinosomes) that range in diameter from 0.2 to 5.0 μm.

Macropinocytic flux

The rate at which macropinocytosed macromolecules are converted into nutrients that are exported to the cytosol; variables contributing to the rate of flux include uptake, evasion of endocytic recycling, catabolism to monomers in lysosomes and release into the cytosol.

Na+/H+ exchanger

(NHE). Plasma membrane protein that promotes exchange of protons for sodium ions; NHE proteins play a key role in maintaining cellular pH.

Necrotic cell debris

Physical remnants of cells that have died from a metabolic crisis or fragmented following apoptosis (secondary necrosis).

Exosomes

Small cell-derived vesicles released into the microenvironment that can contain metabolic intermediates, sugars, RNAs (for example, microRNAs), DNA and intact proteins.

Entosis

The invasion of a living cell into another cell; engulfed ‘loser’ cells can either escape back to the microenvironment or be degraded and provide nutrients to the ‘winner’ cell.

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Finicle, B.T., Jayashankar, V. & Edinger, A.L. Nutrient scavenging in cancer. Nat Rev Cancer 18, 619–633 (2018). https://doi.org/10.1038/s41568-018-0048-x

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