OBJECTIVE: Appropriate clinical management of cases of FIGO Grade I and II endometrial carcinoma relies heavily on the determination of myometrial invasion (MI). There are no reports addressing expression of the cell adhesion molecule CD44 in the subset of Grade I and II endometrioid carcinoma (EC) as it relates to prognosis, including MI. METHODS: Immunohistochemical staining for CD44s and CD44v6 was evaluated in 40 hysterectomy specimens with Grade I and II EC, including 11 noninvasive ECs, 14 with MI 50%). Staining characteristics according to the presence of MI and vascular space invasion (VSI) were evaluated. Strong membranous staining of >10% of tumor cells was interpreted as positive. RESULTS: CD44v6 staining was positive in 20% (8/40) of cases, including 45% (5/11) of EC without MI but only 10% (3/29) with MI (P = 0.025). CD44v6 staining was not present in deeply invasive tumors (0/15), while it was present in 8/25 superficially or noninvasive tumors (P = 0.016). Sensitivity and specificity were 25 and 100%, respectively, using CD44v6 in evaluating deep myometrial invasion. CD44s showed a trend toward positive staining when comparing noninvasive versus invasive tumors and noninvasive/superficially invasive versus deeply invasive tumors (P = 0.08 and 0.12, respectively). CD44s or CD44v6 staining was highly specific for absence of VSI, although statistical comparison did not reach significance. CONCLUSION: Deeply invasive EC was associated with a consistent lack of CD44v6 expression. This may have potential clinical utility if this finding is demonstrated in further study of prehysterectomy sampling specimens containing EC.
It is well known that hyaluronic acid and its principal receptor, CD44, are implicated in the regulation of the tissue repair process, but their role in the formation of chronic diabetic ulcers has not been studied. Hyaluronic acid metabolism and CD44 expression are regulated by lactate, where their increased production is considered to affect the properties of fibroblasts in non-insulin-dependent diabetes mellitus. The aim of our work was to investigate the possible role of hyaluronic acid and CD44, and their regulation by lactate, in the abnormal wound healing of diabetes. Fibroblasts were derived from uninjured skin from four non-insulin-dependent diabetic patients with ulcers and four without ulcers; and from four healthy age-matched volunteers. We observed that diabetic fibroblasts of both groups produced more L-lactate ( approximately 30%) and incorporated more (3)H-glucosamine into the medium hyaluronic acid ( approximately 28%) than controls. Fibroblasts of the diabetic group with ulcers, unlike those of the group without ulcers, showed significant increases in the high molecular weight hyaluronic acid accumulation in the pericellular matrix (30.5%, p
Hyaluronic acid (HA) is a straight chain glycosaminoglycan polymer composed of repeating units of the disaccharide [-D-glucuronic acid-beta1,3-N-acetyl-D-glucosamine-beta1,4-]n, and is found in vertebrates and certain microorganisms. The molecular weight of HA chains is usually equal to approximately 1-10 and MDa, n > 10(3-4), although it can exists as oligosaccharides under some physiological and pathological conditions. HA resides on the cell surface or in the extracellular space, but it also occurred inside the mammalian cells. HA is synthesized in mammals by three enzymes with polymers of varying chain length. The biological functions of HA include the maintenance of elastoviscosity of liquid connective tissues, control of tissue hydration, supramolecular assembly of proteoglycans in the extracellular matrix and besides numerous receptor-mediated functions in cell attachment, mitosis, migration, tumor development, wound healing and inflammation. The extensive repertoire of biological functions of HA corresponds to the existence of a large repertoire of HA-binding proteins (hyaladherins). Many hyaladherins contain a common structural domain, termed a Link module, which is involved in ligand binding. The most important member of the Link module superfamily is the main HA receptor, CD44. CD44 has diverse functions including not only the organization and metabolism of extracellular matrix, but also engage the cytoskeleton and co-ordinate signaling events to enable the cell responce to changes in the environment. HA has an extraordinary high rate of turnover, and at the cellular level it is considered to be degraded progressively by a series of enzymatic reactions that generate polymers of decreasing sizes. HA biological effects are known to be determined by the polymer size and depend on the cell type. For example, the native high molecular weight HA is anti-angiogenic, while its degradation products (6-20 saccharides) stimulate endothelial cell proliferation, migration and differentiation. In contrast, these fragments inhibit the proliferation of vascular smooth muscle cells, whereas high molecular weight HA promotes cell growth and migration. The dysregulation of HA metabolism is a typical feature of diabetes complications, and increased glucose level is considered to be the main cause of this phenomenon. The HA depolymerization due to the effect of free radicals and advanced glycation end products leads to the vitreous body liquefaction, and may be the reason of the proliferative retinopathy in diabetes. The enrichment of extracellular matrix with high molecular weight HA under the action of high glucose level was demonstrated for vascular smooth muscle cells, skin fibroblasts, endothelial and mesangial cells. This effect is considered to accelerate the development of atherosclerosis stimulating the proliferation of vascular smooth muscle cells, and to promote the transformation of acute wounds into chronic ulcers deepening the pathological state of dermal fibroblasts in diabetes. And, on the contrary, the accumulation of high molecular weight HA on the surface of endothelial cells may have positive value for the glycocalyx integrity. Since high molecular weight HA is known to possess the anti-inflammatory and anti-fibrotic effect, the enrichment of mesangial matrix with it may represent an endogenous mechanism to limit renal injury in diabetes. Thus, the investigation of HA metabolism in diabetes mellitus emphasizes the dependence of HA biological effects on cell type and demonstrates the importance of this molecule for tissue homeostasis.