Understanding Keloid Pathobiology From a Quasi-Neoplastic Perspective: Less of a Scar and More of a Chronic Inflammatory Disease With Cancer-Like Tendencies

Abstract

Keloids are considered as benign fibroproliferative skin tumors growing beyond the site of the original dermal injury. Although traditionally viewed as a form of skin scarring, keloids display many cancer-like characteristics such as progressive uncontrolled growth, lack of spontaneous regression and extremely high rates of recurrence. Phenotypically, keloids are consistent with non-malignant dermal tumors that are due to the excessive overproduction of collagen which never metastasize. Within the remit of keloid pathobiology, there is increasing evidence for the various interplay of neoplastic-promoting and suppressing factors, which may explain its aggressive clinical behavior. Amongst the most compelling parallels between keloids and cancer are their shared cellular bioenergetics, epigenetic methylation profiles and epithelial-to-mesenchymal transition amongst other disease biological (genotypic and phenotypic) behaviors. This review explores the quasi-neoplastic or cancer-like properties of keloids and highlights areas for future study.

Regulation of glycolysis and the Warburg effect in wound healing

“…Excessive scarring can occur in the form of keloids, which recapitulate the major clinical features associated with benign skin tumors, including uncontrolled growth, invasion of normal tissues, and recurrence despite treatment (2,3). In addition to gross and histological similarities, keloids exhibit metabolic and inflammatory alterations that parallel those seen in tumors such as chronic inflammation and an unstimulated increase in glucose uptake (25,26). Owing to its tumor-like dependence on glucose, we hypothesized that development of keloids is predicated on greater posttrauma glucose availability, uptake, and upregulation of key glycolytic enzymes in burn skin.…”

Treatment of keloids using 5‐fluorouracil in combination with crystalline triamcinolone acetonide suspension: evaluating therapeutic effects by using non‐invasive objective measures

“…Treatment of excessive scarring, in particular keloids, remains difficult. Even though a significant number of patients benefit from conventional therapeutic approaches such as cryotherapy and intralesional corticosteroids, 17 there are still a significant number of keloids that appear not responding to these approaches or that reoccur after initially successful treatments 18 . 5‐FU has been utilized for the treatment of keloids for many years 4 .…”

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

“…While the above discrepancy still awaits an answer, a related question is raised as to whether autonomy can also be extricated from immortality, although this segregation collides with the facts that human cancers rarely regress spontaneously and that no human tumor shows this segregation. A keloid scar may be the only tumor-like lesion in the human we know that seems to show this extrication, as it shows functional autonomy by constant collagen production without showing clear immortality of its fibroblasts [502][503][504]. Some animal models seem to show this extrication as well: epithelial cells have been shown to be evasive, disseminating, and able to enter into the bloodstream before they form primary tumors [715]; and mammary epithelial cells can be manipulated to metastasize and colonize in the lungs before they are malignantly transformed [716,717].…”

“…While the tumor is still small without invasion or metastasis, a virulently high level of the hormone it secreted may have already killed the patient. Keloid scar, which is not classified as tumor in pathology textbooks but show neoplastic features such as recurrence and incurability, may be an example of uncontrolled function of benign lesion [502][503][504], as its fibroblasts constantly produce collagen. Moreover, uncontrolled function may sometimes show as uncontrolled metabolisms, embodied by such as cachexia-incurring cancers that elicit high metabolic rates to cannibalize many cells of the patient for energy.…”