The biology of cancer: metabolic reprogramming fuels cell growth and proliferation

doi:10.1016/J.CMET.2007.10.002

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The biology of cancer: metabolic reprogramming fuels cell growth and proliferation

Journal Article•DOI•

The biology of cancer: metabolic reprogramming fuels cell growth and proliferation

Ralph J. DeBerardinis¹, Julian J. Lum¹, Georgia Hatzivassiliou¹, Craig B. Thompson¹•Institutions (1)

University of Pennsylvania¹

01 Jan 2008-Cell Metabolism (Cell Press)-Vol. 7, Iss: 1, pp 11-20

TL;DR: This review examines the idea that several core fluxes, including aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis, form a stereotyped platform supporting proliferation of diverse cell types and regulates regulation of these fluxes by cellular mediators of signal transduction and gene expression.

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About: This article is published in Cell Metabolism.The article was published on 2008-01-01 and is currently open access. It has received 3526 citations till now. The article focuses on the topics: PI3K/AKT/mTOR pathway & Lipid biosynthesis.

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Journal Article•DOI•

Hallmarks of cancer: the next generation.

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Douglas Hanahan¹, Robert A. Weinberg²•Institutions (2)

ISREC¹, Massachusetts Institute of Technology²

04 Mar 2011-Cell

TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

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51,099 citations

Cites background from "The biology of cancer: metabolic re..."

...Glycolytic fueling has been shown to be associated with activated oncogenes (e.g., RAS, MYC) and mutant tumor suppressors (e.g., TP53) (DeBerardinis et al., 2008; Jones and Thompson, 2009), whose alterations in tumor cells have been selected primarily for their benefits in conferring the hallmark capabilities of cell proliferation, avoidance of cytostatic controls, and attenuation of apoptosis....
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...Most notable is a DNAdamage sensor that functions via the TP53 tumor suppressor (Junttila and Evan, 2009); TP53 induces apoptosis by upregulating expression of the Noxa and Puma BH3-only proteins, doing so in response to substantial levels of DNA breaks and other chromosomal abnormalities....
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...Similarly, TP53 null mice develop normally, show largely proper cell and tissue homeostasis, and again develop abnormalities later in life, in the form of leukemias and sarcomas (Ghebranious and Donehower, 1998)....
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...…can be further accentuated under the hypoxic conditions that operate within many tumors: the hypoxia response system acts pleiotropically to upregulate glucose transporters and multiple enzymes of the glycolytic pathway (Semenza, 2010a; Jones and Thompson, 2009; DeBerardinis et al., 2008)....
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...Alternatively, in the face of alarm signals indicating overwhelming or irreparable damage to such cellular subsystems, TP53 can trigger apoptosis....
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Journal Article•DOI•

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

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Matthew G. Vander Heiden¹, Lewis C. Cantley¹, Craig B. Thompson²•Institutions (2)

Harvard University¹, University of Pennsylvania²

22 May 2009-Science

TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.

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Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

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12,380 citations

Journal Article•DOI•

Blinded by the Light: The Growing Complexity of p53

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Karen H. Vousden, Carol Prives¹•Institutions (1)

Columbia University¹

01 May 2009-Cell

TL;DR: Control of p53's transcriptional activity is crucial for determining which p53 response is activated, a decision that must be understood if the next generation of drugs that selectively activate or inhibit p53 are to be exploited efficiently.

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2,775 citations

Cites background from "The biology of cancer: metabolic re..."

...Cell 137, May 1, 2009 ©2009 Elsevier Inc. 423 work with p53 to produce a specific cellular response (Figure 5)....
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...418 Cell 137, May 1, 2009 ©2009 Elsevier Inc....
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...414 Cell 137, May 1, 2009 ©2009 Elsevier Inc. PUMA null mice showed that the induction of PUMA by p53 is necessary for the apoptotic response to p53 activation in many tissues (Yu and Zhang, 2003)....
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...Similarly, the ability of p53 to impede glycolysis can help control oncogenic transformation, but the consequent promotion of alternative metabolic pathways (such as the pentose phosphate pathway) might also drive the anabolism necessary for tumor cell growth (DeBerardinis et al., 2008)....
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...Cell 137, May 1, 2009 ©2009 Elsevier Inc. 417 mutant p53 proteins (Morselli et al., 2008), although whether this activity helps malignant progression is not yet known....
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Journal Article•DOI•

The Warburg Effect: How Does it Benefit Cancer Cells?

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Maria V. Liberti¹, Jason W. Locasale¹•Institutions (1)

Duke University¹

01 Mar 2016-Trends in Biochemical Sciences

TL;DR: Several proposed explanations for the function of Warburg Effect are analyzed, emphasize their rationale, and discuss their controversies.

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2,712 citations

Cites methods from "The biology of cancer: metabolic re..."

...In this scenario, the increased glucose consumption is used as a carbon 108 source for anabolic processes needed to support cell proliferation [17, 26-32]....
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Journal Article•DOI•

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

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Sophia Y. Lunt¹, Matthew G. Vander Heiden²•Institutions (2)

Massachusetts Institute of Technology¹, Harvard University²

10 Oct 2011-Annual Review of Cell and Developmental Biology

TL;DR: In this paper, the authors provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass.

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Abstract: Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why in...

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2,251 citations

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References

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Journal Article•DOI•

On the origin of cancer cells.

[...]

Otto Warburg¹•Institutions (1)

Max Planck Society¹

24 Feb 1956-Science

10,654 citations

Journal Article•DOI•

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer.

[...]

Dennis J. Slamon¹, William Godolphin², Lovell A. Jones, John A. Holt³, Steven G. Wong¹, Duane E. Keith¹, Wendy J. Levin¹, Susan G. Stuart, Judy Udove⁴, Axel Ullrich⁵, Michael F. Press⁴ - Show less +7 more•Institutions (5)

University of California, Los Angeles¹, University of British Columbia², University of Chicago³, University of Southern California⁴, Genentech⁵

12 May 1989-Science

TL;DR: The concept that the HER-2/neu gene may be involved in the pathogenesis of some human cancers, including breast and ovarian cancer, is supported.

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Abstract: Carcinoma of the breast and ovary account for one-third of all cancers occurring in women and together are responsible for approximately one-quarter of cancer-related deaths in females. The HER-2/neu proto-oncogene is amplified in 25 to 30 percent of human primary breast cancers and this alteration is associated with disease behavior. In this report, several similarities were found in the biology of HER-2/neu in breast and ovarian cancer, including a similar incidence of amplification, a direct correlation between amplification and over-expression, evidence of tumors in which overexpression occurs without amplification, and the association between gene alteration and clinical outcome. A comprehensive study of the gene and its products (RNA and protein) was simultaneously performed on a large number of both tumor types. This analysis identified several potential shortcomings of the various methods used to evaluate HER-2/neu in these diseases (Southern, Northern, and Western blots, and immunohistochemistry) and provided information regarding considerations that should be addressed when studying a gene or gene product in human tissue. The data presented further support the concept that the HER-2/neu gene may be involved in the pathogenesis of some human cancers.

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6,938 citations

Journal Article•DOI•

Targeting HIF-1 for cancer therapy

[...]

Gregg L. Semenza¹•Institutions (1)

Johns Hopkins University School of Medicine¹

01 Oct 2003-Nature Reviews Cancer

TL;DR: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion.

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Abstract: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

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6,024 citations

"The biology of cancer: metabolic re..." refers background in this paper

...In mammalian cells, this response is coordinated by the hypoxia-inducible factor 1 (HIF-1) transcription factor complex (Gordan and Simon, 2007; Semenza, 2003)....
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Journal Article•DOI•

High frequency of mutations of the PIK3CA gene in human cancers

[...]

Yardena Samuels¹, Zhenghe Wang¹, Alberto Bardelli¹, Natalie Silliman¹, Janine Ptak¹, Steve Szabo¹, Hai Yan², Adi F. Gazdar³, Steven M. Powell⁴, Gregory J. Riggins¹, James K V Willson, Sanford D. Markowitz⁵, Kenneth W. Kinzler¹, Bert Vogelstein¹, Victor E. Velculescu¹ - Show less +11 more•Institutions (5)

Johns Hopkins University¹, Duke University², University of Texas Southwestern Medical Center³, University of Virginia⁴, Case Western Reserve University⁵

23 Apr 2004-Science

TL;DR: To determine if PI3Ks are genetically altered in tumorigenesis, they were sequenced in human for the first time and the results allowed us to assess the importance of phosphatidylinositol 3-kinases in neoplasia.

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Abstract: Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate signaling pathways important for neoplasia, including cell proliferation, adhesion, survival, and motility ([ 1 ][1]–[ 3 ][2]). To determine if PI3Ks are genetically altered in tumorigenesis, we sequenced PI3K genes in human

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3,396 citations

Journal Article•DOI•

HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia

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Jung Whan Kim¹, Irina Tchernyshyov¹, Gregg L. Semenza, Chi V. Dang•Institutions (1)

Johns Hopkins University School of Medicine¹

01 Mar 2006-Cell Metabolism

TL;DR: A hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production is revealed.

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3,193 citations

"The biology of cancer: metabolic re..." refers background in this paper

...HIF-1 induces expression of pyruvate dehydrogenase kinase 1 (PDK1), which phosphorylates and inhibits the PDH complex (Kim et al., 2006; Papandreou et al., 2006)....
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