Biphasic α2ß1 Integrin Expression in Breast Cancer Metastasis to Bone.

Integrins participate in the pathogenesis and progression of tumors at many stages during the metastatic cascade. However, current evidence for the role of integrins in breast cancer progression is contradictory and seems to be dependent on tumor stage, differentiation status, and microenvironmental influences. While some studies suggest that loss of α2ß1 enhances cancer metastasis, other studies suggest that this integrin is pro-tumorigenic. However, few studies have looked at α2ß1 in the context of bone metastasis. In this study, we aimed to understand the role of α2ß1 integrin in breast cancer metastasis to bone. To address this, we utilized in vivo models of breast cancer metastasis to bone using MDA-MB-231 cells transfected with an α2 expression plasmid (MDA-OEα2). MDA cells overexpressing the α2 integrin subunit had increased primary tumor growth and dissemination to bone but had no change in tumor establishment and bone destruction. Further in vitro analysis revealed that tumors in the bone have decreased α2ß1 expression and increased osteolytic signaling compared to primary tumors. Taken together, these data suggest an inverse correlation between α2ß1 expression and bone-metastatic potential. Inhibiting α2ß1 expression may be beneficial to limit the expansion of primary tumors but could be harmful once tumors have established in bone.

Role of integrins in the carcinogenesis of squamous cell carcinoma of the tongue and lower lip.

OBJECTIVE AND METHODS: This study analyzed the distribution, intensity, and pattern of immunohistochemical expression of α2ß1, α3ß1, and α5ß1 integrins in squamous cell carcinoma (SCC) of the lower lip and tongue to identify biomarkers that reflect the clinical course of this cancer. Immunoexpression was compared considering prognostic parameters such as anatomic site, metastasis, and histologic grade of malignancy. RESULTS: Immunohistochemical analysis at the invasion front showed a predominance of granular cytoplasmic expression of the integrins studied. In most cases, immunopositive cells were diffusely distributed in the tumors, irrespective of their location, except for α3ß1 integrin-positive cells which were focally distributed in 53.3% of tongue SCC cases. With respect to staining intensity, positive staining for α2ß1 integrin was observed in 80% of lower lip SCCs and in 93.3% of tongue SCCs. Staining for α3ß1 integrin was moderately positive in 60% of lower lip and tongue SCCs. The staining intensity of α5ß1 integrin was moderately and strongly positive in 53.3% and 46.7% of lower lip SCCs, respectively, and in 46.7% and 53.3% of tongue SCCs. CONCLUSIONS: The strong immunoreactivity for integrins α2ß1, α3ß1, and α5ß1 seen in the oral SCC cases studied suggests a significant participation of these proteins in oral carcinogenesis. However, their expression does not reflect the clinical course of this cancer.

Immunoexpression of α2ß1, α3ß1, and α5ß1 integrins in pleomorphic adenoma and adenoid cystic carcinoma.

The aim of the present study was to compare the expression of α2ß1, α3ß1, and α5ß1 integrins between 28 pleomorphic adenomas (PAs) and 10 adenoid cystic carcinomas (ACCs), and investigate differences in the expression of these integrins according to histologic subtypes of ACCs. It was taken into consideration the presence or absence, distribution, and localization of integrin immunoexpression. There was immunoreactivity in the intercellular contacts of the strands, nests, and solid sheets of PAs, as well as in the luminal and nonluminal cells of the duct-like structures, with a predominant immunoexpression in the luminal cells. The immunoexpression in ACCs varied with histologic subtype of the tumor. It was verified for a tendency of absence and/or reduced expression of all integrins in the solid subtype of ACCs. In general, PAs revealed a more diffuse and remarkable immunoexpression of all studied integrins than ACCs. The reduced integrins expression in ACC may be related to a lesser degree of cell differentiation in this neoplasm. Moreover, the absence and/or reduced expression of the studied integrins in solid ACC suggest a possible role in pathogenesis and more aggressive biological behavior of this histologic subtype.

Genetic variability in platelet integrin α2ß1 density: possible contributor to Plasmodium vivax-induced severe thrombocytopenia.

Understanding the pathogenesis of Plasmodium vivax malaria is challenging. We hypothesized that susceptibility to P. vivax-induced thrombocytopenia could be associated with polymorphisms on relevant platelet membrane integrins: integrin α2 (C807T), and integrin ß3 (T1565C). Although ß3 polymorphism was not related with P. vivax malaria, α2 807T carriers, which show high levels of integrin α2ß1, had a higher probability for severe thrombocytopenia than wild-type carriers. This evidence of the association of integrin polymorphism and P. vivax morbidity was further demonstrated by a moderate but significant correlation between clinical disease and surface levels of the integrin α2ß1.

Enzymes that hydrolyze adenine nucleotides in platelets and polymorphisms in the alpha2 gene of integrin alpha2beta1 in patients with von Willebrand disease.

Von Willebrand disease (VWD) is one of the most common inherited bleeding diseases caused by a qualitative or quantitative deficiency of the von Willebrand factor (FvW). FvW is a multimeric glycoprotein synthesized by megakaryocytes and endothelial cells and it is present in the subendothelial matrix, blood plasma, platelets, and endothelium. This glycoprotein plays an important role in thrombus formation by initiating platelet adhesion to sites of injury as well as platelet aggregation. The aim of this study was to evaluate the activities of enzymes that hydrolyze adenine nucleotides in platelets, ristocetin-induced platelet aggregation (RIPA), and polymorphisms of the alpha2 gene of alpha2beta1 integrin from VWD patients. Platelet nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase, and ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP) activities were verified in 14 VWD patients. For RIPA determination, a final concentration of 1.25 mg/ml of ristocetin was used. Polymorphisms of the alpha2 gene were analyzed through PCR. Platelet NTPDase and E-NPP were decreased in VWD patients. 5'-Nucleotidase activity was not statistically significant between controls and VWD patients. RIPA was significantly reduced, with an allelic frequency of 78.57% for 807C in VWD patients. Our results indicated reduced platelet NTPDase and E-NPP activities which might be related to the low platelet adhesiveness. The prevalence of the 807C allele might account for the variability in bleeding in VWD.

Ameloblastoma and adenomatoid odontogenic tumor: the role of alpha2beta1, alpha3beta1, and alpha5beta1 integrins in local invasiveness and architectural characteristics.

Ameloblastoma is an odontogenic neoplasm characterized by local invasiveness and a tendency toward recurrence, whereas adenomatoid odontogenic tumor (AOT) is an indolent neoplasm. The objective of the present study was to immunohistochemically analyze the role of alpha2beta1, alpha3beta1, and alpha5beta1 integrins in the cellular events and cell-matrix interactions that occur in these tumors and their consequent repercussions on the architectural arrangement and biologic behavior of these lesions. Paraffin-embedded specimens from 30 ameloblastomas (20 solid and 10 unicystic tumors) and 12 AOTs were submitted to immunohistochemistry using the catalyzed signal amplification system. A difference in the pattern of integrin expression was observed between the various histologic types of ameloblastoma. No significant difference in labeling intensity was observed between unicystic and solid ameloblastomas, but comparison between ameloblastomas and AOT showed a significantly stronger expression of alpha5beta1 integrin in the former (P < .05). Our findings suggest an important role of the integrins studied in the architectural characteristics of ameloblastomas and AOTs and a possible participation of alpha5beta1 integrin in the mechanism of local invasion of ameloblastomas.

Cell adhesion and cytotoxicity studies over polyanionic collagen surfaces with variable negative charge and wettability.

This work describes the cytotoxicity, and the cell adhesion behavior of K562 cell line from human erythroleukemia transfected with the DNA for the alpha(2)beta(1) integrin over type-I collagen matrices with variable degree of carboxyl group and wettability. The results showed that type-I collagen materials with variable degree of carboxyl group prepared by selective hydrolysis of carboxyamide side chains of Asn and Gln residues present in the protein, independently from the extent of side chain hydrolysis, was characterized by preserved triple helix structure for materials with a carboxyl group content up to 87 +/- 17. Imbibition and wettability increased linearly with increasing carboxyl group content from 46 +/- 12 to 87 +/- 17, and no signs of cytotoxicity were detected. Nevertheless, in comparison to native collagen, K562 cell adhesion to PACMs was significantly improved by factors ranging from 1.60 to 1.47x, with the reduction in cell adhesion observed with increasing carboxyl content attributed to a balance between the inhibition of increasing negative charge and the stimulation by increased wettability. On the other hand, the overall improvement of K562 cell adhesion to polyanionic collagen was attributed to the introduction of new distinct motifs described as the minimal active recognition sequence for alpha(2)beta(1) integrins binding with type-I collagen produced as a result of Asn-Gly Glu-Ala alpha2(I)294-297, and Gly Gln-Arg-Gly Val-Val carboxyamide side chains hydrolysis.