Abstract
BackgroundEquine sarcoids are locally invasive, fibroblastic benign skin tumors. Bovine papillomavirus type-1 (BPV-1) and/or Bovine papillomavirus type-2 (BPV-2) are believed to be the causative agent of sarcoids, although the mechanisms by which the virus induce the tumor are still poorly understood. We hypothesized that in genetically predisposed equines latent BPV infection may be reactivated by immunosoppression and/or mechanical injury leading to a form of pathologic wound which may transform into a sarcoid. In this study, we investigated in 25 equine sarcoids and in five normal skin samples the histological features and evaluated the immunohistochemical and molecular expression of type I and type III Collagen, vimentin (VIM), alfa Smooth Muscle Actin (α-SMA), Matrix Metalloproteinase (MMPs) -2, 9, 14 and tissue inhibitor of metalloproteinase 2 (TIMP-2).ResultsIn 64 % of investigated sarcoids, type I collagen staining was stronger than that of type III collagen. In 80 % of sarcoids, SFs were strongly positive for vimentin and negative for α-SMA; the remaining sarcoid samples (20 %) showed 70–80 % of SFs labeled for vim and approximately 20–30 % labeled for α-SMA. Moreover, all sarcoid specimen showed a variable staining pattern (weak to moderate) for MMP-9 and MMP-14, and a moderate to strong staining for MMP-2 and TIMP-2. Biochemical analysis confirmed immunohistochemical results and showed in sarcoids, for the first time, the cleaved form of MMP9, the 35 KDa active species for MMP-9.ConclusionsThis study revealed that in equine sarcoids exhibit an altered turnover of the Extracellular Matrix (ECM) deposition and degradation, as result of an altered expression of MMPs and TIMPs. Therefore, these observations seem to confirm that the basic mechanism for growth of equine sarcoids could be a neoplastic transformation during wound healing.
Highlights
Equine sarcoids are locally invasive, fibroblastic benign skin tumors
The hypothesis that cancer may be “a wound that won’t heal” has been supported by numerous studies [14,15,16] suggesting that wound healing and tumorigenesis share consistently similarities in terms of histological features and signaling molecules; those are among others Matrix Metalloproteinases (MMPs), a family of at least 25 zinc-dependent endopeptidases, and their inhibitors (TIMPs) all essentially capable of degrading Extracellular Matrix (ECM), including collagen
We speculate that changes of the expression levels and of the enzymatic activity of MMP-2, MMP-9, MMP-14 (MMP1MMT) and tissue inhibitor of metalloproteinase (TIMP)-2 may play an important role in the pathogenesis of sarcoids, being responsible for ECM turnover
Summary
Equine sarcoids are locally invasive, fibroblastic benign skin tumors. Bovine papillomavirus type-1 (BPV-1) and/or Bovine papillomavirus type-2 (BPV-2) are believed to be the causative agent of sarcoids, the mechanisms by which the virus induce the tumor are still poorly understood. Martano et al BMC Veterinary Research (2016) 12:24 genetically predisposed horses, BPV-1/BPV2 may be responsible for abnormal fibroblast proliferation on one hand, and on the other for alterations in dynamics of the extracellular matrix (ECM) and its main components (e.g. collagen) These changes could induce an alteration of the wound healing process and may be an important factor in the pathogenesis of equine sarcoids. Of the growing family of MMPs, MMP-2 (gelatinase A, 72-kDa type IV collagenase,) and MMP-9 (gelatinase B, 92-kDa type IV collagenase) are unique for their fibronectin-like collagen binding domains and are responsible of degradation of type IV collagen in the basement membranes and in fibrillar collagens, which are essential features of tissue repair and remodeling processes Their activity is controlled by a group of protein inhibitors, the TIMPs. MMP-14 is a trans-membrane protease, capable of degrading different ECM components such as collagen types I, II, and III, as well as fibronectin and laminin [20]. The enzymatic activities of MMP-2 and MMP-9 were quantified by gelatinzymography of the same homogenized tumour tissues
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