Tumor transformation causes significant wound healing failure; always consider this when a wound fails to heal as expected.

There is always a reason why a wound does not heal. Furthermore, the relationship between a normal healing process and the development of a de novo tumor within the wound bed is well recognized. It has been said that a wound is a tumor that heals and a tumor is a wound that does not heal and it is this relationship that arises in the horse in particular. Mesenchymal stem cells (MSC’s) that localize at perivascular sites respond rapidly to external stimuli and with the vascular and immune systems lead to successful wound healing. Cancer in some circumstances can be considered to be a wound that never heals; this is accompanied by changes in MSCs that parallel the wound-healing response. MSCs are now recognized as key players in tumorigenesis (Li et al., 2019). It is easy to imagine that the healing process can be transformed into an unstable genetic situation culminating in primary tumorigenesis. Tumor dormancy is also considered to be one of the major unsolved questions in cancer biology. Increasing evidence points to tissue trauma and subsequent wound healing as contributing events in escape from dormancy leading to tumor development.

It is important to identify the common regulators of wound repair and tumor formation and to unravel their functions and mechanisms of action. The recognized factors that are involved in inhibiting wound healing are shown in Table 1. This table illustrates the diagnostic process that should be considered when a wound fails to heal; there are clear relationships between the various factors making the management of non-healing wounds problematic. For sure, tumor transformation is a very serious long-term challenge and while tumor cells exist in the wound bed, healing will be inhibited usually to a significant degree either focally or more generally in the periphery or the wound bed or both.

Although neoplastic reasons for wound healing failure are probably are they are extremely important since no matter what other measures are undertaken the wound will not heal if any component of neoplastic tissue is present. Of course, there are several pathways that have an influence on the healing process in respect of neoplastic inhibition of wound healing.

1. The systemic cancer case: The first is the concept that horses with significant tumors affecting any part of the body are likely to have paracrine/paraneoplastic subtle effects on the function of the immune system and specifically on wound healing. Wounds on unhealthy horses often fail to heal. There are many complex reasons for this. Advanced age, immunosuppression, malnutrition, and co-morbidity, particularly with systemic tumors such as lymphoma often have a profound influence on the healing process. Wounds do not present detached from the patient! There is always a horse involved and so it is incumbent upon the clinician to examine the patient to establish the presence of factors that might inhibit the healing process including neoplastic disease. However, systemic or cutaneous neoplasia is not always obvious and in the former group, paraneoplastic signs may be all that are detectable clinically at the time.
2. Tumor development within a wound site (spontaneous tumorigenesis): The link between wound healing and tumorigenesis has attracted much attention in the human medical sphere. ( Dillekås & Straume, 2019) Following an acute injury, resident and non-resident cell populations instigate the natural [beneficial] wound healing responses; classically these involve temporary, controlled, and coordinated increases in inflammation, extracellular matrix production, and proliferation with the objective of restoring normal organ architecture leading to a functional repair. However, the ongoing failure of wound healing evokes a perpetuating wound-healing response in which cytokine activity, including low-grade persistence of TGF-β, is abnormal (Wilmink, van Weeren et al., 1999) promoting the development of fibrosis, organ failure, and cancer.
3. Toll-like receptors (TLRs) act as sensors of danger signals in injured tissue to switch the wound healing response toward fibrogenesis and regeneration as a protective response to imminent danger at the cost of an increased long-term risk of developing cancer transformation.

Hemangiosarcoma is probably the third most common tumor transformation in a wound site (Figure 2). It is perhaps a little more understandable than the other tumor types in view of the prominent role neovascularisation has in the healing process as mentioned above.

The traumatized cancer site: Here the tumor pre-exits the wound either obviously or undetectably. Traumatizing a tumor is a well-recognized cause of tumor progression. A good example of this is the equine sarcoid; here this effect is very common. In this situation, it is likely that the vast majority of affected sites that are traumatized, either accidentally or intentionally by incomplete surgical removal or by biopsy (without the expectation of a total tumor removal of course), results in an “expected” significant exacerbation of the tumor both in growth rate and aggression.

As might be expected incomplete removal of tumor results in a failed surgical site – even a single cell can create a significant delay in healing and oftentimes the proliferation of the tumor is often mistaken for [exuberant] granulation tissue (Figure 5).

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