Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Metastasis

Metastasis to bone: causes, consequences and therapeutic opportunities

Nature Reviews Cancer volume 2, pages 584–593 (2002)Cite this article

Key Points

  • Common tumours, such as those of the breast, lung and prostate, frequently metastasize to bone, and in many patients with advanced disease the skeleton is the site of the most significant tumour burden.

  • There are different patterns of bone effects in patients with cancer, ranging from purely or mostly destructive or osteolytic (breast cancer, myeloma), to mostly bone-forming or osteoblastic (prostate cancer).

  • In the case of breast-cancer-causing osteolysis, the main mediator is parathyroid-hormone-related peptide (PTHrP), whereas, in osteoblastic lesions, known mediators include endothelin-1 and platelet-derived growth factor.

  • In osteolytic metastasis, there is a 'vicious cycle' in the bone microenvironment, whereby bi-directional interactions between tumour cells and osteoclasts lead to both osteolysis and tumour growth.

  • The molecular mechanisms that are responsible for this vicious cycle are now being clarified and involve tumour-cell production of PTHrP and bone-derived growth factors that are released as a consequence of increased bone resorption.

  • Bisphosphonates interrupt the vicious cycle and cause not only a reduction in osteolytic bone lesions, but also decrease the tumour burden in bone.

  • More-effective treatments for interruption of the vicious cycle are now being developed, including specifically neutralizing antibodies to PTHrP and more efficacious osteoclast inhibitors.

Abstract

The most common human cancers — lung, breast and prostate — have a great avidity for bone, leading to painful and untreatable consequences. What makes some cancers, but not others, metastasize to bone, and how do they alter its physiology? Some of the molecular mechanisms that are responsible have recently been identified, and provide new molecular targets for drug development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Types of bone metastasis.
Figure 2: The steps involved in tumour-cell metastasis from a primary site to the skeleton.
Figure 3: The RANK–RANKL system in osteolytic bone metastases.
Figure 4: Model for osteoblastic bone metastases caused by prostate cancer.
Figure 5: The 'vicious cycle' hypothesis of osteolytic metastases.

Similar content being viewed by others

Article 15 October 2020

Robert E. Coleman, Peter I. Croucher, … Luis Costa

References

  1. Wingo, P. A., Tong, T. & Bolden, S. Cancer statistics, 1995. CA Cancer J. Clin. 45, 8–30 (1995).

    Article  CAS  Google Scholar 

  2. Mantyh, P. W., Clohisy, D. R., Kotzenburg, M. & Hunt, S. P. Molecular mechanisms of cancer pain. Nature Rev. Cancer 2, 201–209 (2000).

    Article  Google Scholar 

  3. Honore, P. et al. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nature Med. 6, 521–528 (2000).Evidence that the bone-resorption inhibitor osteoprotegerin inhibits not just osteolysis but also bone pain in metastatic bone disease.

    Article  CAS  Google Scholar 

  4. Boyde, A., Maconnachie, E., Reid, S. A., Delling, G. & Mundy, G. R. Scanning electron microscopy in bone pathology: review of methods, potential and applications. Scan. Electron Microsc., 1537–1554 (1986).This paper shows, by scanning electron microscopy, evidence of osteoclastic resorption pits at bone metastatic sites, indicating the importance of osteoclasts as cellular mediators of osteolysis.

  5. Stewart, A. F. et al. Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity. J. Clin. Endocrinol. Metab. 55, 219–227 (1982).Histomorphometric evidence of the abnormalities in osteoblastic and osteolytic activity that occurs in patients with bone metastases. This was shown by observing the impaired osteoblastic response to increased osteoclastic resorption.

    Article  CAS  Google Scholar 

  6. Charhon, S. A. et al. Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma special reference to osteomalacia. Cancer 51, 918–924 (1983).

    Article  CAS  Google Scholar 

  7. Garnero, P. et al. Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br. J. Cancer 82, 858–864 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Koga, H. et al. Use of bone turnover marker, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), in the assessment and monitoring of bone metastasis in prostate cancer. Prostate 39, 1–7 (1999).

    Article  CAS  Google Scholar 

  9. Koizumi, M. et al. Dissociation of bone formation markers in bone metastasis of prostate cancer. Br. J. Cancer 75, 1601–1604 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Percival, R. C. et al. Biochemical and histological evidence that carcinoma of the prostate is associated with increased bone resorption. Eur. J. Surg. Oncol. 13, 41–49 (1987).One of the first studies to indicate that osteoblastic metastases are accompanied by increased bone resorption in patients with prostate cancer.

    CAS  Google Scholar 

  11. Yoshida, K. et al. Serum concentration of type I collagen metabolites as a quantitative marker of bone metastases in patients with prostate carcinoma. Cancer 80, 1760–1767 (1997).

    Article  CAS  Google Scholar 

  12. Pelger, R. C., Hamdy, N. A., Zwinderman, A. H., Lycklama a Nijeholt, A. A. & Papapoulos, S. E. Effects of the bisphosphonate olpadronate in patients with carcinoma of the prostate metastatic to the skeleton. Bone 22, 403–408 (1998).

    Article  Google Scholar 

  13. Yi, B. et al. PDGF in breast cancer promotes osteosclerotic bone metastases. J. Bone Min. Res. 15 (Suppl 1) A1035 (2000).

    Google Scholar 

  14. Adami, S. Bisphosphonates in prostate carcinoma. Cancer 80, 1674–1679 (1997).

    Article  CAS  Google Scholar 

  15. Liotta, L. A. & Kohn, E. C. The microenvironment of the tumour–host interface. Nature 411, 375–379 (2001).An excellent review that cites evidence for the importance of the stroma in cancer-cell behaviour at primary and metastatic sites.

    Article  CAS  Google Scholar 

  16. Liotta, L. A. & Kohn, E. Cancer invasion and metastases. JAMA 263, 1123–1126 (1990).

    Article  CAS  Google Scholar 

  17. Fidler, I. J. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res. 38, 2651–2660 (1978).

    CAS  Google Scholar 

  18. Zetter, B. R. The cellular basis of site-specific tumor metastasis. N. Engl. J. Med. 322, 605–612 (1990).

    Article  CAS  PubMed  Google Scholar 

  19. Southby, J. et al. Immunohistochemical localization of parathyroid hormone-related protein in breast cancer. Cancer Res. 50, 7710–7716 (1990).

    CAS  Google Scholar 

  20. Powell, G. J. et al. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res. 51, 3059–3061 (1991).Clinical data that shows evidence for increased PTHrP expression in bone metastatic sites in patients with breast cancer.

    CAS  Google Scholar 

  21. Bryden, A. A., Hoyland, J. A., Freemont, A. J., Clarke, N. W. & George, N. J. Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases. Br. J. Cancer 86, 322–325 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Miki, T., Yano, S., Hanibuchi, M. & Sone, S. Bone metastasis model with multiorgan dissemination of human small-cell lung cancer (SBC-5) cells in natural killer cell-depleted SCID mice. Oncol. Res. 12, 209–217 (2001).

    Article  Google Scholar 

  23. Henderson, M. et al. Parathyroid hormone-related protein production by breast cancers, improved survival, and reduced bone metastases. J. Natl Cancer Inst. 93, 234–237 (2001).

    Article  CAS  Google Scholar 

  24. Guise, T. A. et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast-cancer-mediated osteolysis. J. Clin. Invest. 98, 1544–1549 (1996).Human breast cancer cells, when inoculated into the systemic circulation of nude mice, cause osteolytic lesions that are abrogated by neutralizing antibodies to the tumour peptide PTHrP.

    Article  CAS  PubMed  Google Scholar 

  25. Stewart, A. F. PTHrP (1–36) as a skeletal anabolic agent for the treatment of osteoporosis. Bone 19, 303–306 (1996).

    Article  CAS  Google Scholar 

  26. Zhang, Q. X., Borg, A., Wolf, D. M., Oesterreich, S. & Fuqua, S. A. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 57, 1244–1249 (1997).

    CAS  Google Scholar 

  27. De Larco, J. E. et al. A potential role for IL-8 in the metastatic phenotype of breast carcinoma cells. Am. J. Pathol. 158, 639–646 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Downey, S. E. et al. Expression of the receptor for parathyroid hormone-related protein in normal and malignant breast tissue. J. Pathol. 183, 212–217 (1997).

    Article  CAS  Google Scholar 

  29. Gallwitz, W. E. et al. Low doses of 6-thioguanine and 6–mercaptoguanosine inhibit osteolytic bone disease caused by human breast cancer. J. Bone Min. Res. 15 (Suppl. 1), S200 (2000).

    Google Scholar 

  30. Ogata, E. PTHrP, paraneoplastic syndrome and cancer metastasis. J. Bone Min. Metab, 19 (Suppl. 1), S1–S2 (2001).

    Google Scholar 

  31. Zhang, J. et al. Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J. Clin. Invest. 107, 1235–1244 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Nelson, J. B. et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nature Med. 1, 944–949 (1995).

    Article  CAS  Google Scholar 

  33. Yin, J. J. et al. Endothelin A receptor blockade inhibits osteoblastic metastases. J. Bone Min. Res. 15 (Suppl. 1), 1254 (2000).

    Google Scholar 

  34. Yin, J. J. et al. Osteoblastic bone metastases: tumor-produced endothelin-1 mediates new bone formation via the endothelin A receptor. J. Back Musculoskeletal. Rehabil. 14 (Suppl. 1), F400 (1999).Data confirming the molecular mechanisms that are responsible for the 'vicious cycle' in breast cancer metastasis to bone.

    Google Scholar 

  35. Marcelli, M. et al. A single nucleotide substitution introduces a premature termination codon into the androgen receptor gene of a patient with receptor-negative androgen resistance. J. Clin. Invest. 85, 1522–1528 (1990).

    Article  CAS  PubMed  Google Scholar 

  36. Marquardt, H., Lioubin, M. N. & Ikeda, T. Complete amino acid sequence of human transforming growth factor type-β2. J. Biol. Chem. 262, 12127–12131 (1987).

    CAS  Google Scholar 

  37. Harris, S. E. et al. Effects of transforming growth factor-β on bone nodule formation and expression of bone morphogenic protein 2, osteocalcin, osteopontin, alkaline phosphatase, and type 1 collagen mRNA in long-term cultures of fetal rat calvarial osteoblasts. J. Bone Miner. Res. 9, 855–863 (1994).

    Article  CAS  Google Scholar 

  38. Rabbani, S. A. et al. An amino-terminal fragment of urokinase isolated from a prostate cancer cell line (PC-3) is mitogenic for osteoblast-like cells. Biochem. Biophys. Res. Commun. 173, 1058–1064 (1990).

    Article  CAS  Google Scholar 

  39. Achbarou, A. et al. Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res. 54, 2372–2377 (1994).

    CAS  Google Scholar 

  40. Rabbani, S. A. et al. Structural requirements for the growth factor activity of the amino-terminal domain of urokinase. J. Biol. Chem. 267, 14151–14156 (1992).

    CAS  Google Scholar 

  41. Dallas, S. L. et al. Characterization and autoregulation of latent TGF-β complexes in osteoblast-like cell lines: production of a latent complex lacking the latent TGF-β-binding protein (LTBP). J. Biol. Chem. 269, 6815–6822 (1994).

    CAS  Google Scholar 

  42. Dallas, S. L. et al. Dual role for the latent transforming growth actor-β binding protein in storage of latent TGF-β in the extracellular matrix and as a structural matrix protein. J. Cell Biol. 131, 539–549 (1995).

    Article  CAS  Google Scholar 

  43. Cramer, S. D., Chen, Z. & Peehl, D. M. Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP stimulated cAMP accumulation in mouse osteoblasts. J. Urol. 156, 526–531 (1996).

    Article  CAS  Google Scholar 

  44. Iwamura, M., Hellman, J., Cockett, A. T., Lilja, H. & Gershagen, S. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Urology 48, 317–325 (1996).

    Article  CAS  Google Scholar 

  45. Matuo, Y. et al. Heparin binding affinity of rat prostate growth factor in normal and cancerous prostate: partial purification and characterization of rat prostate growth factor in the Dunning tumor. Cancer Res. 47, 188–192 (1987).

    CAS  Google Scholar 

  46. Mansson, P. E. et al. HBGF1 gene expression in normal rat prostate and two transplantable rat prostate tumors. Cancer Res. 49, 2485–2494 (1989).

    CAS  Google Scholar 

  47. Canalis, E. et al. Effects of endothelial cell growth factor on bone remodeling in vitro. J. Clin. Invest. 79, 52–58 (1987).

    Article  CAS  PubMed  Google Scholar 

  48. Canalis, E., Centrella, M. & McCarthy, T. Effects of basic fibroblast growth factor on bone formation in vitro. J. Clin. Invest. 81, 1572–1577 (1988).

    Article  CAS  PubMed  Google Scholar 

  49. Mayahara, H. et al. In vivo stimulation of endosteal bone formation by basic fibroblast growth factor in rats. Growth Factors 9, 73–80 (1993).

    Article  CAS  Google Scholar 

  50. Dunstan, C. R. et al. Systemic administration of acidic fibroblast growth factor (FGF-1) prevents bone loss and increases new bone formation in ovariectomized rats. J. Bone Miner. Res. 14, 953–959 (1999).

    Article  CAS  Google Scholar 

  51. Izbicka, E. et al. Human amniotic tumor which induces new bone formation in vivo produces a growth regulatory activity in vitro for osteoblasts identified as an extended form of basic fibroblast growth factor (bFGF). Cancer Res. 56, 633–636 (1996).

    CAS  Google Scholar 

  52. Yi, B., Williams, P. J., Niewolna, M., Wang, Y. & Yoneda, T. Tumor-derived PDGF-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. Cancer Res. 62, 917–923 (2002).

    CAS  Google Scholar 

  53. Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, 571–573 (1889).The classical paper describing the 'seed and soil' hypothesis of tumour-cell metastasis.

    Article  Google Scholar 

  54. Yin, J. J. et al. TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest. 103, 197–206 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Hiraga, T., Williams, P. J., Mundy, G. R. & Yoneda, T. The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases. Cancer Res. 61, 4418–4424 (2001).

    CAS  Google Scholar 

  56. Rasmussen, A. A. & Cullen, K. J. Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors. Breast Cancer Res. Treat. 47, 219–233 (1998).

    Article  CAS  Google Scholar 

  57. Yu, H. & Rohan, T. Role of the insulin-like growth factor family in cancer development and progression. J. Natl Cancer Inst. 92, 1472–1489 (2000).

    Article  CAS  Google Scholar 

  58. Sasaki, A. et al. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res. 55, 3551–3557 (1995).In a preclinical model of human breast cancer metastasis to bone, bisphosphonates reduce not only osteolysis but also tumour burden.

    CAS  Google Scholar 

  59. Diel, I. J. et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N. Engl. J. Med. 339, 357–363 (1998).The authors show, in a controversial study, that the bisphosphonate clodronate reduces tumour burden in both bone and non-bone metastatic sites in patients with breast cancer.

    Article  CAS  Google Scholar 

  60. Powles, T. J. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 91, 730 (1999).

    Article  CAS  Google Scholar 

  61. Saarto, T., Blomqvist, C., Virkkunen, P. & Elomaa, I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J. Clin. Oncol. 19, 10–17 (2001).

    Article  CAS  Google Scholar 

  62. Griepp, P. et al. A single subcutaneous dose of an osteoprotegerin (OPG) construct (AMGN–0007) causes a profound and sustained decrease of bone resorption comparable to standard intravenous bisphosphonate in patients with multiple myeloma. Blood 92 (Suppl. 1), A3227 (1998).

    Google Scholar 

  63. Oyajobi, B. O. et al. Therapeutic efficacy of a soluble receptor activator of nuclear factor-κB–IgG-Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy. Cancer Res. 61, 2572–2578 (2001).

    CAS  Google Scholar 

  64. Kuehl, W. M. & Bergsagel, P. L. Multiple myeloma: evolving genetic events and host interactions. Nature Rev. Cancer 2, 175–187 (2002).

    Article  CAS  Google Scholar 

  65. Seyberth, H. W. et al. Prostaglandins as mediators of hypercalcemia associated with certain types of cancer. N. Engl. J. Med. 293, 1278–1283 (1975).

    Article  CAS  Google Scholar 

  66. Lee, M. V., Fong, E. M., Singer, F. R. & Guenette, R. S. Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res. 61, 2602–2608 (2001).

    CAS  Google Scholar 

  67. Sanders, J. L. et al. Extracellular calcium-sensing receptor expression and its potential role in regulating parathyroid hormone-related peptide secretion in human breast cancer cell lines. Endocrinology 141, 4357–4364 (2000).

    Article  CAS  Google Scholar 

  68. Sanders, J. L., Chattopadhyay, N., Kifor, O., Yamaguchi, T. & Brown, E. M. Ca2+-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells. Am. J. Physiol. Endocrinol. Metab. 281, E1267–E1274 (2001).

    Article  CAS  Google Scholar 

  69. Moseley, J. M. et al. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc. Natl Acad. Sci. USA 84, 5048–5052 (1987).

    Article  CAS  Google Scholar 

  70. Stewart, A. F., Wu, T., Goumas, D., Burtis, W. J. & Broadus, A. E. N-terminal amino acid sequence of two novel tumor-derived adenylate cyclase-stimulating proteins: identification of parathyroid hormone-like and parathyroid hormone-unlike domains. Biochem. Biophys. Res. Commun. 146, 672–678 (1987).

    Article  CAS  Google Scholar 

  71. Strewler, G. J. et al. N-terminal amino acid sequence of two novel tumor-derived adenylate cyclase stimulating proteins: idenfication of parathyroid hormone-unlike domains. Biochem. Biophys. Res. Commun. 146, 672–678 (1987).

    Article  Google Scholar 

  72. Yates, A. J. P. et al. Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption and bone metabolism. J. Clin. Invest. 81, 932 (1988).

    Article  CAS  PubMed  Google Scholar 

  73. Mundy, G. R. Calcium Homeostasis: Hypercalcemia and Hypocalcemia 2nd edn (Martin Dunitz, London, 1990).

    Google Scholar 

  74. Mundy, G. R., Wilkinson, R. & Heath, D. A. Comparative study of available medical therapy for hypercalcemia of malignancy. Am. J. Med. 74, 421–432 (1983).

    Article  CAS  Google Scholar 

  75. Silverman, I. E. & Flynn, J. A. Images in clinical medicine. Ivory vertebra. N. Engl. J. Med. 338, 100 (1998).

    Article  CAS  Google Scholar 

  76. Fidler, I. J. Modulation of the organ microenvironment for treatment of cancer metastasis. J. Natl Cancer Inst. 87, 1588–1592 (1995).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, MS 7877, San Antonio, 78229-3900, Texas, USA

    Gregory R. Mundy

Authors
  1. Gregory R. Mundy
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

Cancer.gov

bone cancer

breast cancer

lung cancer

myeloma

ovarian carcinoma

pancreatic carcinoma

prostate cancer

renal carcinoma

LocusLink

alkaline phosphatase

BMP2

BMP3

BMP4

BMP6

type I collagen

endothelin-1

endothelin-A receptor

ERBB2

FGF1

FGF2

hepatocyte growth factor

IGF1

IGFBPs

IKK

IL-1

IL-6

IL-8

IL-11

IL-18

JUN

lymphotoxin

MAPK

MIP1α

NF-kB

oestrogen receptor

OPG

osteocalcin

PDGF

PSA

PTHrP

RANK

RANKL

SMAD

TGF-α

TGF-β

TGF-β2

uPA

Medscape DrugInfo

alendronate

pamidronate

OMIM

Paget's disease

FURTHER INFORMATION

Medline Plus Bone Cancer Site

University of Michigan Comprehensive Cancer Center — Bone Metastasis Facts

Glossary

LEUKOERYTHROBLASTIC ANAEMIA

A type of anaemia that is associated with cancers that involve the bone marrow, and that is accompanied by increased production of white blood cells.

ALKALINE PHOSPHATASE

An enzyme that is found on the cell surface of osteoblasts, is involved in bone mineralization and is used as a serum marker of increased osteoblast activity.

BONE-SCANNING AGENTS

Agents, such as bisphosphonates, which localize to bone, that can be tagged with an isotope that allows their detection by imaging techniques. These are used in clinical medicine to detect sites of active bone turnover or bone disease.

OSTEOCALCIN

A protein constituent of bone. Its function remains to be clarified, but circulating levels are used as a marker of osteoblast activity.

MYELOMA

A neoplastic disorder of the plasma cells that is associated with extensive bone destruction and production of large amounts of specific immunoglobulins.

CALVARIA

The skull bones. Rodent calvaria are frequently used in organ culture experiments to determine the effects of factors or compounds that stimulate or inhibit bone resorption or bone formation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mundy, G. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2, 584–593 (2002). https://doi.org/10.1038/nrc867

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc867

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing