Wound healing and cancer; two sides of the same coin?

We are imperfect beings. We do silly, reckless things, or sometimes-just fall up the stairs; but either way, we get injured and those injuries must heal. Wound healing is just one of the many outputs of our body’s ability to regenerate, which is pretty remarkable in itself. Regeneration is achieved through functional stem cells resident in our tissues. These stem cells haven’t differentiated, they haven’t committed to any one path, so they are able to duplicate and produce new tissue. For instance, there are two types of stem cells in your skin, epidermal stem cells and hair follicle stem cells. Each is responsible for generating a certain kind of tissue. Hair follicle stem cells keep your hair growing, and epidermal stem cells rejuvenate your skin with new cells. This is their normal day-to-day function; my skin is slowly replaced and I’m not stuck with a bad haircut for the rest of my life.

When things get a little too imperfect, they are also there to save the day. If the epidermis is damaged and an open cut needs to be healed, both types of stem cells can kick into action to regenerate and repair the skin. Based on signals from near by tissue, these cells know when to turn off this rapid regeneration, they can sense when enough cells have been made to heal the wound. Suppose these amazing, regenerating cells didn’t stop; what would happen if they lost the ability to pick up on these cues?

Cancer is a complicated and case-specific disease, but one common thread is that these are aggressive cells that grow without ‘listening’ to near by tissues telling them to stop. It has been described as “a wound that never heals”, and with good reason; there are some strange links between wound healing and cancer. Observationally it has been noted that individuals with chronic wounds have increased risk of cancer. Conversely, genetically inhibiting wound healing in mice reduces the likelihood of that animal developing cancer1. Given what we now know about stem cells and their regenerative abilities, there may be a clear biological link.

Ge and colleagues published an article directly addressing the behaviors of epidermal and hair follicle stem cells in wound healing and cancer2. Theses authors have some astonishing findings. First, during wound healing hair follicle stem cells can lose their identity, they can temporarily become epithelial stem cells to generate skin instead of hair. Once the wound is healed, these cells reassume their molecular identity and resume their existence as a hair follicle cell. This means that the three dimensional organization of their DNA actually changes during this time and key epithelial gene programs are turned on. When the wound heals, a molecular switch is flipped and this all returns back to the original hair follicle stem cell state.

The authors also examined a specific form of cancer known as small cell carcinoma. It was observed that this cancer type shares the molecular signatures of both hair follicle stem cells and epidermal stem cells. The argument made is that when wounded, cell fate barriers are transiently removed to rapidly fix a tissue, resulting in a highly proliferative and adaptive stem cell. However, in wound healing, the epithelial and hair follicle programs regulate each other. In malignancies, this regulation is lost. The up shot is that genetically interfering with these wound healing molecular signatures in cancer cells limits the tumor growth, and this is an area where new therapeutics are greatly needed.

Getting a severe wound is not going to give you cancer, but as Ge et al. illustrated, there is a mechanistic link between the two. As scientists better understand these pathways and the molecular switches, they can move towards enhanced wound healing technologies and cancer treatments.

  1. Schober, Markus, and Elaine Fuchs. “Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling.” Proceedings of the National Academy of Sciences 108.26 (2011): 10544-10549.
  2. Ge, Yejing, et al. “Stem Cell Lineage Infidelity Drives Wound Repair and Cancer.” Cell (2017).