New genomic research has increased the understanding of surprising links between diabetic foot ulcers (DFUs) and carcinomas.
Investigators at University of Miami Miller School of Medicine have identified a microRNA tumor suppressor that is distinct to DFUs. miR193b-3p controlled excessive proliferation and migration in DFUs and may be a therapeutic target in the context of wound healing induction and cancer therapeutics/diagnostics.
"Tumors and wounds have been connected in the past but not from the perspective of a chronic wound like diabetic foot ulcers, which would appear to essentially hold everything we need to control transformation to cancer," principal investigator, Marjana Tomic-Canic, professor and chair of the Wound Healing and Regenerative Medicine Research Program, University of Miami Miller School of Medicine on wound healing, told BioWorld Science.
The team reported its results in the May 11, 2022, issue of Science Translational Medicine.
The 5-year mortality rate for DFUs is in fact higher than that of breast cancer and prostate cancer combined, in part because nonhealing DFUs go unrecognized due to insensitivity from peripheral neuropathy. All too often the infection becomes septic to ultimately cause death.
There has been a tremendous investment in wound studies, with over 150 studies of either leg ulcers or DFUs in progress as of 2017. Still, there are no reliably effective treatments for healing refractory DFUs, and there has not been a single FDA-approved treatment for chronic wounds since the approval of recombinant PDGF gel (becaplermin) 25 years ago.
While growth factors appeared great in mouse models of DFU extended in numerous studies performed, the same approaches did not work in patients because of differences in rodent versus human tissue biology.
The work now published in Science Translational Medicine originated after 20 years of focus by Tomic-Canic.
In clinical DFUs there is a low incidence of forming tumors, but when the biological makeup of DFUs is examined at the molecular signature level, one would expect to have lots of tumors because of the nearly uncontrollable hyperproliferative epidermis. The cells do not execute either the healing or the cancer transformation program.
"DFUs have figured out how to really inhibit the processes that you want to inhibit in cancer because if you think about a tumor, what you need for a tumor is proliferation, migration and angiogenesis. All of that is inhibited in diabetic foot ulcers. So that's the basis of our conceptual approach," Tomic-Canic said. "In wound healing, these processes are very tightly controlled temporally and spatially in terms of how the cells divide, migrate and get a new vascular supply to ultimately rebuild the epithelial cornified barrier. A normal wound is unlike diabetic foot ulcers... In DFUs you still have the same processes going on, but they never stopped healing. On the flip side DFUs have figured out how to suppress all the transformation processes that you see in cancer."
The investigators started by comparing DFU gene expression profiles to squamous cell carcinomas. The miRNA miR193b-3p was highly activated in the context of DFUs, but not the carcinoma. They also showed that miR193b-3p was not found in either acute wounds or venous leg ulcers, another type of chronic wound of similar anatomical localization.
The miR193b-3p was previously determined to be a tumor suppressor in multiple different tumor types and was shown to target the oncogenes KRAS and KIT among others in the study.
In the study the investigators discovered that the tumor suppressor miR193b-3p functioned as a dominant inhibitor of epithelial migrations. This trade-off reduced tumor incidence, but that prevents wound healing to ultimately confer the increased mortality risk.
The miR193b-3p affects multiple targets at the same time by binding the 3' end of many mRNAs. Tomic-Canic emphasized that this has the potential to be either beneficial or dangerous depending on the context. Going forward, the investigators will focus on understanding the roles of miR193b-3p on multiple cell types. Ultimately the translational goal would be to manipulate miR193b-3p levels to maintain tumor suppression while will allowing the nontransformed cells to move to heal the DFU.
Secondly, she wanted to stress that the importance of understanding the differences between DFUs and transformed squamous cell types holds the main keys to determining how to inhibit tumor growth. Still, Tomic-Canic qualified, "This is just tip of the iceberg that we have discovered, and it just provides another piece in the jigsaw puzzle to promoting DFU healing, while promoting tumor suppression, but... it's not going to be the answer to it all."