Age-related skin changes may contribute to melanoma metastases among older adults
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Age-related changes to the skin’s elasticity may drive higher rates of metastatic skin cancer among older individuals, according to study results.
Increased stiffness in aging skin leads to elevated production of a protein called ICAM1.
Increases in ICAM1 concentration trigger the growth of blood vessels in a tumor, facilitating its growth. ICAM1 also causes blood vessels to become “leaky,” which induces tumor cells to escape and circulate throughout the body more easily.
Ashani Weeraratna, PhD, associate director for laboratory research at the Kimmel Center and professor of oncology at Johns Hopkins University School of Medicine, led the study.
Weeraratna’s laboratory is focused on the effects of age-related changes on the spread of melanoma tumors and their resistance to cancer therapies.
Prior analyses by the Weeraratna laboratory showed a protein called HAPLN1 helps maintain the structure of the extracellular matrix, which preserves skin elasticity. Age-related decreases in HAPLN1 release leads to stiffening of the skin.
In this study, researchers found that the stiffening caused by decreased HAPLN1 alters cellular signaling, which leads to increases in ICAM1 levels. This increase in ICAM1 drives tumor angiogenesis.
“These findings suggest that tumors in aged individuals are more aggressive because they have more blood vessels, and those vessels are leakier, allowing for tumor cells to move in and out of them more easily,” Weeraratna told Healio. “We are interested in understanding how this age-related angiogenesis impacts other age-related diseases. We are also interested in seeing if we can translate our findings into the clinic.”
Healio spoke with Weeraratna about the rationale for this study and the implications of the findings.
Healio: What prompted you to conduct this study?
Weeraratna: Our previous work — published in Cancer Discovery in 2019 and in Clinical Cancer Research in 2020 — showed that lymphatic vessel integrity was impacted by aging, and that angiogenesis was increased in tumors in the elderly. One of the reviewers of the latter paper asked us if those new blood vessels were leakier. That launched this project, driven by the question of whether the aging extracellular matrix affect blood vessel integrity.
Healio: Prior to this study, what had been known about the protein ICAM1 and its effect on tumor growth?
Weeraratna: ICAM1 is known to impact the ability of immune cells to move in and out of the bloodstream and, therefore, is thought to play roles in tumor immunity.
Healio: How did you conduct the study?
Weeraratna: We used a mixture of in vitro and in vivo approaches focusing on understanding the interaction between normal, noncancer-associated fibroblasts and their interaction with endothelial cells, and then expanding those analyses to tumors in mice. Healio: What did you find?
Weeraratna: As we age, our skin becomes stiffer due to the loss of HAPLN1, which basically acts as a knitting needle to knit together collagen, elastin and hyaluronic acid. When the skin becomes stiffer, endothelial cells sitting on those matrices are less able to hold on to each other tightly, and the blood vessels become leaky and more permeable. ICAM1 also is involved in this process, as it is increased when endothelial cells lie down on stiff surfaces. Targeting ICAM1 can reduce tumor angiogenesis.
Healio: What are the next steps in research?
Weeraratna: We are interested in understanding how this age-related angiogenesis impacts other age-related diseases. We are also interested in seeing if we can translate our findings into the clinic.
References:
- Ecker BL, et al. Cancer Discov. 2019;doi:10.1158/2159-8290.CD-18-0168.
- Fane ME, et al. Clin Cancer Res. 2020;doi:10.1158/1078-0432.CCR-20-0446.
- Johns Hopkins Medicine. Age-related changes in skin may contribute to melanoma metastases (press release). Available at: https://www.hopkinsmedicine.org/news/newsroom/news-releases/2024/03/age-related-changes-in-skin-may-contribute-to-melanoma-metastases. Posted March 12, 2024. Accessed April 18,2024.
- Marino-Bravante GE, et al. Nat Aging. 2024;doi:10.1038/s43587-024-00581-8.
For more information:
Ashani Weeraratna, PhD, can be reached at aweerar1@jhu.edu.
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