Inflammation in RDEB may favor skin cancer growth: Mouse study
Weakened immunity in skin also could contribute to disease progression
Inflammation occurring early in the course of recessive dystrophic epidermolysis bullosa (RDEB) may create conditions for the disease to progress and for cancer to grow in the skin, a mouse study suggests.
Although further studies are necessary, the findings “underscore the essential role of inflammation in RDEB pathophysiology [disease] and suggest a pathway to the development of a protumor microenvironment,” the scientists wrote.
The study, “Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin,” was published by an international team of researchers in Frontiers in Immunology.
‘Proinflammatory environment’ found in RDEB mice
RDEB, a severe form of epidermolysis bullosa, occurs due to mutations in the COL7A1 gene. This codes for part of type VII collagen, the protein that helps hold the layers of skin together. When type VII collagen is missing, the skin becomes fragile and prone to tears and blisters.
People with RDEB also are at risk of developing squamous cell carcinoma, a type of malignant or cancerous tumor that begins in flat cells in the top layer of the skin.
A tumor develops due to certain changes within the genes of a cell or a group of cells. While inflammation is known to be important for a tumor to grow and spread, it’s not clear whether it may play a role before the tumor forms.
In a bid to find out, the researchers used a technique called single-cell RNA sequencing to study the activity of genes in individual skin cells of young mice lacking part of both copies of the COL7A1 gene. These mice were used as a model of RDEB.
Compared with wild-type or healthy mice, samples of paw skin tissue from 11-day-old RDEB mice had more fibroblasts — the cells in the connective tissue that make collagen proteins — and perivascular cells, which are those that wrap around blood vessels. These RDEB mice also had more immune cells than did the wild-type mice.
Single-cell RNA sequencing revealed that genes known as hallmark signatures of cancer — including certain genes involved in angiogenesis, or the formation of new blood vessels, and inflammation — were more active across all types of cells in RDEB mice versus wild-type.
“These data confirmed the existence of an early proinflammatory environment in RDEB,” the team wrote.
Immune-suppressed skin could contribute to cancer, RDEB progression
When the researchers looked more closely at the fibroblasts, they found two different paths of development. One group of fibroblasts followed a path toward turning into myofibroblasts — a type of fibroblasts that can contract in a way similar to muscle cells.
Another group shared the characteristics of inflammatory fibroblasts seen in other inflammatory diseases, as well as in inflammatory cancer-associated fibroblasts. These are triggered by interleukin (IL)-1, an inflammatory cytokine or signaling protein.
These data suggest “a potential role of inflammation, driven by the chronic release of inflammatory cytokines such as IL-1, in creating an immune-suppressed dermal [skin] microenvironment that underlies RDEB disease progression,” the team wrote.
Moreover, the data “suggest a pathway to the development of a protumor microenvironment that may underlie the early onset and aggressive nature of RDEB-associated [squamous cell carcinoma],” the investigators added.
This microenvironment was rich in immune cells such as neutrophils and macrophages. While further analyses revealed “dynamic waves” of a number of inflammatory cytokines, IL-1 appeared to have a central role in shaping the dermal microenvironment.
When added to fibroblasts collected from people with RDEB or healthy individuals, IL-1 increased the levels of podoplanin (PDPN) in those fibroblasts to a significantly greater extent. PDPN is a protein that helps cancer cells travel and spread throughout the body.
While the data “provide a frameshift in the understanding of RDEB,” they are “only the tip of the iceberg of the RDEB dermal microenvironment,” the researchers noted, calling for further investigations.