1. Hypoxia-induced HIF1α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis. Pigment Cell & Melanoma Research, 2017; DOI: 10.1111/pcmr.12579
2. Hypoxia-dependent regulation of HIF-1 activity.
Insights provide possible new targets for personalized treatments. Cancerous tumors are voracious. Once they have consumed all the oxygen and nutrients in the original tumor site, the cancer cells metastasize to find more nourishment. Searching for clues about how the body signals the lack of oxygen in melanoma skin cancer, NIH researchers focused on HIF1alpha (hypoxia inducible factor 1 alpha), a protein that acts as a sensor for oxygen and nutrients in many types of cancer. They discovered 40 new genes that are either turned on or off by HIF1alpha, and 10 genes that were associated with the amount of time it took the melanoma to move from the original tumor to the rest of the body.
“These newly identified genes and genetic pathways in primary melanoma could give researchers new targets for developing personalized treatments for melanoma, and potentially other cancers,” said Stacie Loftus, Ph.D. “In addition, changes in how the genes are expressed (turned on or off) could be used in the future to predict how and when the cancer cells will spread to other parts of the body and how fast they will grow.”
The lifetime risk of an individual being diagnosed with melanoma is 2%. With more than 10,130 deaths (and 76,380 new diagnoses) in 2016, melanoma is one of the leading causes of skin cancer-related deaths. Melanoma occurs when melanocytes undergo a malignant transformation. UV rays from the sun and from tanning beds can damage the DNA in skin cells, causing melanoma. If melanoma is caught early, before leaving the skin and moving to lymph nodes and the rest of the body, patients have a 91.5% 5-year survival rate. If the cancer is caught at later stages, the prognosis is only 30 to 60%t 5-year survival rate.
When tumor cells are present in an environment that lacks oxygen and nutrients, they receive a signal that it is time for the cells to move to a different part of the body. Identifying which genes define this critical tumor state provides researchers and clinicians biomarkers of this critical stage of disease progression. In melanoma, biomarkers can be used to determine tumor stage, diagnosis, therapy selection and when to monitor for disease recurrence.
“In many ways, melanoma is a poster child for precision medicine,” Dr. Loftus said. “Current therapies in clinical trials are focused on targeting genetic changes in tumors and helping to boost one’s immune system to fight the cancer cells.” In the next phase of her work, Dr. Loftus and her team will analyze the roles that HIF1alpha and other transcription factors play in turning genes on and off in melanocytes and melanomas. They will also delve into the newly discovered genes regulated by low oxygen levels that are distinct from HIF1alpha to better understand the role they have in tumor progression. https://www.genome.gov/27567794/
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