Understanding How Low Oxygen Levels Promote Spread of Breast Cancer
One of the characteristics of most breast tumors is that regions can become starved for oxygen. This condition, known as hypoxia, is associated with an increased risk that the tumor will spread beyond the breast and eventually lead to death. New research results from the Johns Hopkins Physical Sciences-Oncology Center (PS-OC) has now identified key molecular events triggered by hypoxia and demonstrated how they might enable breast tumor cells to metastasize.
The Johns Hopkins PS-OC team, led by Gregg Semenza and Denis Wirtz, focused their studies on a molecule known as hypoxia-inducible factor-1 alpha (HIF-1), a protein known to activate the transcription of dozens of genes when oxygen levels in a tissue fall below the normal range, and its effects on collagens, the chief components of the extracellular matrix that holds tissues together. The results of these experiments showed that HIF-1 triggers the production of three specific proteins that together cause collagen fibers to align in organized tracks within breast tissues. Such tracks enable malignant cells to migrate through the tissue. Drs. Semenza and Wirtz and their collaborators published their findings in two papers appearing in the Journal of Biological Chemistry and Molecular Cancer Research.
In one set of experiments, Dr. Wirtz, who is the principal investigator for the Johns Hopkins PS-OC, and Dr. Semenza, who is the chief scientific investigator, and their collaborators showed that hypoxia stabilizes HIF-1 and that this in turn increases the levels of collagen prolyl and lysyl hydroxylase enzymes. The collagen prolyl hydroxylases catalyze the laying down new collagen fibers in breast tissue, while the lysyl hydroxylase facilitates alignment of the fibers, which causes breast tissue to stiffen. The researchers showed that this stiff microenvironment enhances breast tumor cell adhesion, elongation, and migration, which in turn, increases tumor progression.
In the second set of experiments, the researchers accumulated further evidence of the critical role that the increase in lysyl hydroxylase production plays in the formation and alignment of collagen fibers and the migration of cancer cells. In addition, they showed that blocking the production of this enzyme inhibited the invasiveness of breast cancer cells and their migration into adjacent fat and muscle tissue.
They also demonstrated, by comparing the expression of the lysyl hydroxylase gene that codes for this enzyme in normal and malignant breast tissue, that expression levels were significantly higher in breast cancer tissue than in normal tissue. By examining patient survival data, they also showed that increased expression of lysyl hydroxylase gene was associated with decreased survival from breast cancer. Further examination showed that breast tumors grown from cells that did not produce lysyl hydroxylase did not metastasize to the lungs or lymph nodes. The Johns Hopkins team noted that eliminating the production of this enzyme had no effect on tumor growth, only on the ability of tumors to metastasize. However, since metastasis is the primary cause of death from breast and most other cancers, these findings could lead to new therapies for fibrotic breast cancers, which have the poorest prognosis and highest rates of recurrence.
This work was supported by the National Cancer Institute's Physical Sciences in Oncology initiative, a program that aims to foster the development of innovative ideas and new fields of study based on knowledge of the biological and physical laws and principles that define both normal and tumor systems. It was detailed in two papers, abstracts of which are available at the journals’ Web sites. The two papers are:
“HIF promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts, which appeared in the Journal of Biological Chemistry. View abstract
“Procollagen lysyl hydroxylase 2 is essential for breast cancer metastasis,” which was published in Molecular Cancer Research. View abstract