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  • Review Article
  • Published:

The anaemia of cancer: death by a thousand cuts

Nature Reviews Cancer volume 5, pages 543–555 (2005)Cite this article

Key Points

  • Anaemia is the most common cancer-associated morbidity.

  • Cancer-associated anaemia is an adverse prognostic factor for survival independent of tumour type.

  • The mechanisms for cancer-associated anaemia are diverse, but the most important is suppression of production of the essential erythroid-cell growth factor erythropoietin.

  • Erythropoietin serves as a survival factor for late-stage erythroid cells by coordinating the expression of both anti-apoptotic and pro-apoptotic proteins in these cells during their differentiation.

  • Tumour cells also have erythropoietin receptors.

  • Anaemia causes tissue hypoxia, which is tumour promoting through activation of genes in addition to erythropoietin that facilitate angiogenesis, glucose metabolism and cell proliferation, as well as selecting for p53-defective cells. Tissue hypoxia also enhances the resistance of tumour cells to radiotherapy or antimetabolites.

  • Recombinant human erythropoietin can alleviate cancer-associated anaemia and tissue hypoxia, but two recent clinical trials indicated that recombinant erythropoietin might also act as a tumour promoter, whereas the use of tumour-necrosis factor-α (TNFα) and TNF-related apoptosis-inducing ligand as antitumour agents could favour the activity of pro-apoptotic proteins during differentiation of erythoid cells.

Abstract

Cancer has a negative systemic impact on its host in addition to its local or metastatic effects, and no cancer complication is more ubiquitous than anaemia, a condition for which there is now a specific remedy, the recombinant growth factor erythropoietin. This is not a trivial therapeutic consideration, because cancer-associated anaemia has an adverse influence on survival regardless of tumour type. However, the pharmacological correction of anaemia with recombinant erythropoietin could promote tumour growth, whereas the use of tumour-necrosis factor-α (TNFα) and TNF-related apoptosis-inducing ligand as antitumour agents could exacerbate anaemia, thereby perpetuating tissue hypoxia and tumour progression.

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Figure 1: The erythroid differentiation pathway.
Figure 2: The feedback relationship between hypoxaemia and erythropoietin production.
Figure 3: Signal transduction mediated by erythropoietin and stem-cell factor in erythroid progenitor cells.
Figure 4: Causes of cancer-associated anaemia.

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Authors and Affiliations

  1. Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, 21210, Maryland, USA

    Jerry L. Spivak

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Jerry L. Spivak is a consultant for Roche

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DATABASES

Entrez Gene

erythropoietin

IL-3

IL-4

IL-9

IL-12

SCF

HIF1α

HIF1β

IFNγ

IL-1

IL-6

TNFα

JAK2

FAS

MIP1α

SDF1α

TP53

Glossary

PARANEOPLASTIC SYNDROMES

Clinical disorders associated with cancer due to abnormalities of endocrine, neurological, musculoskeletal, cardiovascular, dermatological, haematological, gastrointestinal or renal function that are not directly related to direct invasion by the cancer or its metastases.

PROTHROMBOTIC

A clinical state in which there is a risk of inappropriate blood coagulation.

THROMBOPOIETIN

A polypeptide hormone that is responsible for platelet production through its stimulation of megakaryocyte proliferation and maturation.

HAEMATOCRIT

The relative volume of whole blood occupied by erythrocytes expressed as a percentage. That is, a haematocrit of 45% is equivalent to a volume of 45 ml of erythrocytes in 100 ml of blood.

CASPASE

The name of a family of aspartate-specific cysteinyl endoproteases that are involved in the initiation and propagation of apoptosis.

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Spivak, J. The anaemia of cancer: death by a thousand cuts. Nat Rev Cancer 5, 543–555 (2005). https://doi.org/10.1038/nrc1648

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