Tag: melanoma

A New Understanding of How Moles Turn into Melanoma

Melanoma cells. Source: National Cancer Institute.

Moles and melanomas are both skin tumours that come from melanocytes. Moles are usually harmless, while melanomas are cancerous and often deadly without treatment. A study published in eLife Magazine explains how common moles and melanomas form and why sometimes moles turn into melanoma.

Melanocytes produce melanin that protects the skin against UV radiation. Specific changes to the DNA sequence of melanocytes, called BRAF gene mutations, are found in over 75% of moles. The same change is also found in 50% of melanomas and is common in lung, colon and other cancers. It was thought that when melanocytes only have the BRAFV600E mutation the cell stops dividing, resulting in a mole. When melanocytes have other mutations with BRAFV600E, they divide uncontrollably, turning into melanoma. This model is called ‘oncogene-induced senescence’.

“A number of studies have challenged this model in recent years,” said Robert Judson-Torres, PhD, Huntsman Cancer Institute (HCI) researcher and University of Utah (U of U) assistant professor. “These studies have provided excellent data to suggest that the oncogene-induced senescence model does not explain mole formation but what they have all lacked is an alternative explanation – which has remained elusive.”

The study team took moles and melanomas donated by patients and used transcriptomic profiling and digital holographic cytometry. Transcriptomic profiling lets researchers determine molecular differences between moles and melanomas. Digital holographic cytometry helps researchers track changes in human cells.

“We discovered a new molecular mechanism that explains how moles form, how melanomas form, and why moles sometimes become melanomas,” said Prof Judson-Torres.

The study shows that additional mutations for melanocytes to turn into melanoma are not needed, but environmental signalling can be a trigger for the cells. Melanocytes express genes in different environments, instructing them to either divide uncontrollably or stop dividing altogether.

“Origins of melanoma being dependent on environmental signals gives a new outlook in prevention and treatment,” said Prof Judson-Torres. “It also plays a role in trying to combat melanoma by preventing and targeting genetic mutations. We might also be able to combat melanoma by changing the environment.”

These findings create a foundation for researching potential melanoma biomarkers, allowing doctors to spot cancerous changes in the blood sooner. The researchers are also keen to use these data to better understand potential topical agents to reduce risk melanoma risk, delay development, or stop recurrence, and to detect melanoma early.

Source: Huntsman Cancer Institute

Old Antibiotics as New Weapons against Melanoma

Researchers may have hit upon a new weapon in the fight against melanoma: antibiotics that target a vulnerability in the ‘power plants’ of cancer cells when they try to survive cancer therapy.

“As the cancer evolves, some melanoma cells may escape the treatment and stop proliferating to ‘hide’ from the immune system. These are the cells that have the potential to form a new tumor mass at a later stage,” explains cancer researcher and RNA biologist Eleonora Leucci at KU Leuven, Belgium. “In order to survive the cancer treatment however, those inactive cells need to keep their ‘power plants’—the mitochondria—switched on at all times.” As mitochondria derive from bacteria that, over time, started living inside cells, they are very vulnerable to a specific class of antibiotics. This is what gave us the idea to use these antibiotics as anti-melanoma agents.”

The researchers implanted patient-derived tumors into mice, which were then treated with antibiotics, either as alone or in combined with existing anti-melanoma therapies. Leucci observed: “The antibiotics quickly killed many cancer cells and could thus be used to buy the precious time needed for immunotherapy to kick in. In tumors that were no longer responding to targeted therapies, the antibiotics extended the lifespan of—and in some cases even cured—the mice.”

The researchers made use of nearly antibiotics rendered nearly obsolete because of antibiotic resistance. However, this does not affect the efficacy of the treatment in this study, Leucci explained. “The cancer cells show high sensitivity to these antibiotics, so we can now look to repurpose them to treat cancer instead of bacterial infections.”

However, patients with melanoma should not try to experiment, warned Leucci. “Our findings are based on research in mice, so we don’t know how effective this treatment is in human beings. Our study mentions only one human case where a melanoma patient received antibiotics to treat a bacterial infection, and this re-sensitized a resistant melanoma lesion to standard therapy. This result is cause for optimism, but we need more research and clinical studies to examine the use of antibiotics to treat cancer patients. Together with oncologist Oliver Bechter (KU Leuven/UZ Leuven), who is a co-author of this study, we are currently exploring our options.”

Source: KU Leuven

Journal information: Roberto Vendramin et al, Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma, Journal of Experimental Medicine (2021). DOI: 10.1084/jem.20210571

High Melanoma Rates Reported in Sunny US State

A study reports that melanoma mortality among people in Utah, a sunny, high-altitude state, outpaced that of the rest of the country over 1975 to 2013.

This runs counter to the falling melanoma death rates in recent years in both Utah and the United States, a trend likely due to improved treatments such as immunotherapy. It is still the deadliest skin cancer type, with melanoma diagnosis rate in Utah the highest in the US.

Motivation for the research was recent evidence showing that for most of the 1990s and 2000s, even as melanoma mortality in the United States remained constant, incidence increased six-fold. This increasing incidence without accompanying mortality rise indicates overdiagnosis, ie false cancer diagnoses. 

In the case of melanoma, overdiagnosis may result from increased scrutiny, where increasing numbers of biopsies may find a benign lesion that would have gone undetected.

Since Utah has the highest melanoma incidence, a team from Huntsman Cancer Institute (HCI) at the University of Utah set out to evaluate the state’s melanoma diagnosis and death rate data. Biostatistician Kim Herget analysed data from the Utah Cancer Registry, a National Cancer Institute Survival, Epidemiology, and End Results (SEER) database, and the researchers found that in contrast to the rest of the country, melanoma mortality in Utah rose 0.8% per year from 1975 to 2013. Even though Utah’s melanoma death rates have been falling in recent years, they are still higher than the rest of the country.

“Although we agree that overdiagnosis of melanoma is a growing problem, the sustained increase in melanoma mortality in Utah suggests that at least some fraction of the increasing incidence is real and cannot be attributed solely to overdiagnosis,” said Doug Grossman, MD, PhD, who co-leads the HCI melanoma and skin cancer centre at HCI and serves as professor of dermatology at the University of Utah. “Our research underscores an increased risk for Utahns, and so we must remain vigilant about melanoma. For doctors, this means regular conversations with patients about their skin health and family history. For patients, this means practicing sun-safe behaviors like diligent sunscreen use, wearing sun-protective clothing, and monitoring their skin at home on a monthly basis to reduce risk of skin cancer and optimize early detection.”

Future studies should determine whether this trend in people living in Utah results from increased ultraviolet exposure in a mostly fair-skinned population living in a sunny, high-altitude climate or if it is associated with other factors such as environment or genetics. Melanomas are also found at higher rates in immune compromised patients.

Source: Medical Xpress

Journal information: Doug Grossman et al, The Rapid Rise in Cutaneous Melanoma Diagnoses N Engl J Med 2021; 384:e54 DOI: 10.1056/NEJMc2101980