Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Feb;79(5-6):991–995. doi: 10.1038/sj.bjc.6690158

Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast

R D Leek 1,#, R J Landers2 2,#, A L Harris 1, C E Lewis 2
PMCID: PMC2362675  PMID: 10070902

Abstract

Necrosis is a common feature of invasive carcinoma of the breast and is caused by chronic ischaemia leading to infarction. Although necrosis was previously assumed to be due to a generally poor blood supply in the tumour, in this study we show that it is present in tumours with focal areas of high vascular density situated away from the actual sites of necrosis. This may account, in part, for the previous observation that necrosis is linked to poor prognosis in this disease. Highly angiogenic tumours often display blood vessel shunting from one tumour area to another, which further exacerbates ischaemia and the formation of tumour necrosis. We have recently demonstrated that high focal microphage infiltration into breast tumours is significantly associated with increased tumour angiogenesis and poor prognosis and that the macrophages accumulate in poorly vascularized, hypoxic areas within breast tumours. In order to investigate the interactions of macrophages with chronic ischaemia (as reflected by the presence of necrosis) and angiogenesis in breast tumours, we quantified the levels of these three biological parameters in a series of 109 consecutive invasive breast carcinomas. We found that the degree of tumour necrosis was correlated with both microphage infiltration (Mann–Whitney U, P-value = 0.0009; chi-square, P-value = 0.01) and angiogenesis (Mann–Whitney U P-value = 0.0008, chi square P-value = 0.03). It was also observed that necrosis was a feature of tumours possessing an aggressive phenotype, i.e. high tumour grade (chi-square, P-value < 0.001), larger size (Mann–Whitney U, P-value = 0.003) and low oestrogen receptor status (Mann–Whitney U, P-value = 0.008; chi-square, P-value < 0.008). We suggest, therefore, that aggressive tumours rapidly outgrow their vascular supply in certain areas, leading to areas of prolonged hypoxia within the tumour and, subsequently, to necrosis. This, in turn, may attract macrophages into the tumour, which then contribute to the angiogenic process, giving rise to an association between high levels of angiogenesis and extensive necrosis. © 1999 Cancer Research Campaign

Keywords: necrosis, hypoxia, angiogenesis, macrophage, breast cancer

Full Text

The Full Text of this article is available as a PDF (67.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blood C. H., Zetter B. R. Tumor interactions with the vasculature: angiogenesis and tumor metastasis. Biochim Biophys Acta. 1990 Jun 1;1032(1):89–118. doi: 10.1016/0304-419x(90)90014-r. [DOI] [PubMed] [Google Scholar]
  2. Clauss M., Gerlach M., Gerlach H., Brett J., Wang F., Familletti P. C., Pan Y. C., Olander J. V., Connolly D. T., Stern D. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990 Dec 1;172(6):1535–1545. doi: 10.1084/jem.172.6.1535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dachs G. U., Stratford I. J. The molecular response of mammalian cells to hypoxia and the potential for exploitation in cancer therapy. Br J Cancer Suppl. 1996 Jul;27:S126–S132. [PMC free article] [PubMed] [Google Scholar]
  4. Fisher E. R., Anderson S., Redmond C., Fisher B. Pathologic findings from the National Surgical Adjuvant Breast Project protocol B-06. 10-year pathologic and clinical prognostic discriminants. Cancer. 1993 Apr 15;71(8):2507–2514. doi: 10.1002/1097-0142(19930415)71:8<2507::aid-cncr2820710813>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  5. Forsythe J. A., Jiang B. H., Iyer N. V., Agani F., Leung S. W., Koos R. D., Semenza G. L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996 Sep;16(9):4604–4613. doi: 10.1128/mcb.16.9.4604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fox S. B., Leek R. D., Weekes M. P., Whitehouse R. M., Gatter K. C., Harris A. L. Quantitation and prognostic value of breast cancer angiogenesis: comparison of microvessel density, Chalkley count, and computer image analysis. J Pathol. 1995 Nov;177(3):275–283. doi: 10.1002/path.1711770310. [DOI] [PubMed] [Google Scholar]
  7. Harmey J. H., Dimitriadis E., Kay E., Redmond H. P., Bouchier-Hayes D. Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol. 1998 Apr-May;5(3):271–278. doi: 10.1007/BF02303785. [DOI] [PubMed] [Google Scholar]
  8. Helmlinger G., Yuan F., Dellian M., Jain R. K. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 1997 Feb;3(2):177–182. doi: 10.1038/nm0297-177. [DOI] [PubMed] [Google Scholar]
  9. Kato T., Kimura T., Miyakawa R., Tanaka S., Fujii A., Yamamoto K., Kameoka S., Hamano K., Kawakami M., Aiba M. Clinicopathologic study of angiogenesis in Japanese patients with breast cancer. World J Surg. 1997 Jan;21(1):49–56. doi: 10.1007/s002689900192. [DOI] [PubMed] [Google Scholar]
  10. Lee A. H., Happerfield L. C., Bobrow L. G., Millis R. R. Angiogenesis and inflammation in invasive carcinoma of the breast. J Clin Pathol. 1997 Aug;50(8):669–673. doi: 10.1136/jcp.50.8.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Leek R. D., Landers R., Fox S. B., Ng F., Harris A. L., Lewis C. E. Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma. Br J Cancer. 1998 Jun;77(12):2246–2251. doi: 10.1038/bjc.1998.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Leek R. D., Lewis C. E., Whitehouse R., Greenall M., Clarke J., Harris A. L. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 1996 Oct 15;56(20):4625–4629. [PubMed] [Google Scholar]
  13. Lewis C. E., Leek R., Harris A., McGee J. O. Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J Leukoc Biol. 1995 May;57(5):747–751. doi: 10.1002/jlb.57.5.747. [DOI] [PubMed] [Google Scholar]
  14. Negus R. P., Stamp G. W., Hadley J., Balkwill F. R. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. Am J Pathol. 1997 May;150(5):1723–1734. [PMC free article] [PubMed] [Google Scholar]
  15. Nicholson S., Sainsbury J. R., Needham G. K., Chambers P., Farndon J. R., Harris A. L. Quantitative assays of epidermal growth factor receptor in human breast cancer: cut-off points of clinical relevance. Int J Cancer. 1988 Jul 15;42(1):36–41. doi: 10.1002/ijc.2910420108. [DOI] [PubMed] [Google Scholar]
  16. Plate K. H., Warnke P. C. Vascular endothelial growth factor. J Neurooncol. 1997 Dec;35(3):365–372. doi: 10.1023/a:1005845307160. [DOI] [PubMed] [Google Scholar]
  17. Scannell G., Waxman K., Kaml G. J., Ioli G., Gatanaga T., Yamamoto R., Granger G. A. Hypoxia induces a human macrophage cell line to release tumor necrosis factor-alpha and its soluble receptors in vitro. J Surg Res. 1993 Apr;54(4):281–285. doi: 10.1006/jsre.1993.1044. [DOI] [PubMed] [Google Scholar]
  18. Semenza G. L., Roth P. H., Fang H. M., Wang G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994 Sep 23;269(38):23757–23763. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES