ADHESION CONCEPT IN CANCER BIOLOGY: LOCAL AND CENTRAL MECHANISMS (PART 1)

The review presents the concept the key mechanism of the tumor process is a violation of adhesion interactions involving local and central mechanisms. Local features of adhesive dysregulation are demonstrated in the first part. The lack of histospecific adhesion molecules expression resulting from stress or genetic mutation damages an important mechanism of antitumor protection of the tissue disrupting the processes of proliferation and differentiation. The deficiency of histone-specific homotypic adhesion molecules which occurs later exacerbates the disorders. This leads to a decrease in the expression of leukocyte integrins (LFA-1, Mac-1) ligands of the β2 family on the surface of immune effectors and to an increase also in the expression of adhesion molecules to the substrate-antigens VLA (very late activation) family of β1 -integrins on tumor cells. The first restricts the interaction of ICAM family molecules with their contra-receptors from the β2 -integrin family reducing the elimination of target cells by immune effectors which contributes to the screening of the tumor from antitumor surveillance. The second promotes the invasion of the tumor into the surrounding tissues, the formation of blood vessels as well as its heterotypic adhesion with other tissues which further stimulates the proliferation and suppression processes of tumor cells apoptosis. So, the adhesion molecules can be compared to the Phoenix bird: disappearing at the beginning of the process (between the similar cells), they reappear in a new quality (increasing adhesion to cells of other tissues), increasing the totalysm of the tumor. It should be taken into account that tumor cells due to adhesion dysregulation “isolate themselves from society”, lose their differentiation, their maturity and “fall into childhood”, being unable to perform specific, “adult” functions. So, cancer can be considered as a manifestation of the cells aging. Therefore, the anti-stress, endogenous geroprotective mechanisms activation based on the adhesion correction can be effective for preventing and treatment the oncological process.

Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β7 integrin expression

The regulation of integrin expression and function controls interactions of immune cells and targets their trafficking locally and systemically. We show here that the tyrosine phosphatase SHP-1 is required for lymphocyte surface expression of the intestinal immune response-associated integrin β7, but not for β1 or β2 integrins. Viable motheaten mice deficient for SHP-1 have less β7 on T cells and lack β7 on B cells. SHP-1 function is targeted in B cells by the B cell specific lectin CD22 (Siglec-2), suggesting a potential role for CD22 in β7 expression. CD22-deficiency on B cells phenocopies the effects of SHP-1 haplodeficiency. Mechanistically, we show that SHP-1 suppresses β7 endocytosis: internalization of β7 but not β1 integrin is accelerated in SHP-1+/− and CD22−/− B cells. Moreover, mutations in CD22 cytoplasmic SHP1-binding ITIM sequences reduce α4β7 comparably, and loss of CD22 lectin activity has an intermediate effect suggesting a model in which the CD22 ITIM sequences recruit SHP-1 to control β7 expression. Integrin α4β7 selectively contributes to cell interactions in intestinal immunity. Consistent with this, CD22 deficient and SHP-1+/− B cells display reduced β7-dependent homing to gut associated Peyer’s patches (PP); and CD22-deficiency impairs intestinal but not systemic antibody responses and delays clearance of the gut pathogen rotavirus. The results define a novel role for SHP-1 in the differential control of leukocyte integrins and an unexpected integrin β7-specific role for CD22-SHP-1 interplay in mucosal immunity.

Immunoadhesive regulation using multiphytoadaptogene for spontaneous hepatocarcinomas prevention

The purposeof this investigation was to evaluate the efficacy of correcting the LFA-1 and Mac-1 leukocyte integrins expression on peripheral blood cells as well as IL-6 and IL-10 serum levels using liquid form multiphytoadaptogene preventive application for hepatocarcinomas incidence suppression and life-span increase of CBA inbreed mice.Materials and methods.The study was carried out on 439 males of inbred CBA mouse strain (subline CBA/LacY). The experimental mice received 10 % liquid form multiphytoadaptogene complex (MPAC) solution in drinking water during the first month of life including the final time period of liver differentiation (preventive administration). MPAC is the standardized herbal formula composed of 40 plant extracts components including adaptogenes Panax ginseng, Eleutherococcus senticosus, Rhodiola rosea, as well as compounds with phenolic structure (flavonoids, triterpene glycosides, etc). Anti-mutagenic, anti-oxidant, immunomodifying activities of MPAC were demonstrated. The CD11a and CD11b antigens expressions on peripheral blood cells were analyzed by indirect immunofluorescence reaction, serum cytokines IL-6 and IL-10 concentrations were determined by enzyme-linked immunosorbent assay as well as the liver tissue morphology were analyzed at the age of 4, 8, 22 months. Tumor incidence and volumes were evaluated at the age of 8 and 22 months. Motor activity and physical status (body weight, coat state) were estimated in the ontogenesis. The average life-span and survival median was analyzed by the Kaplan–Meier method. Statistical analysis was performed with the program STATISTICA 6.0.Results.Inhibited expression of LFA-1 and Mac-1 leukocyte integrins on peripheral blood cells as well as elevated IL-6 and IL-10 serum levels, high incidence of liver tumors (100 % of mice-males), their high number and big sizes in the late period of postnatal ontogenesis in CBA high-cancer inbrede mice, also as life-span not reaching two years was demonstrated. At the same time plural tumor-infiltrating limphocytes were not found. Short-term MPAC preventive administration (during the first month of mouse life occupying the final differentiation period of liver tissue genetically predisposal to hepatoms incidence) revealed the long-term heterotypic adhesion molecules leukocyte integrins LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) up-regulated expression, providing the contact interactions of immune effectors and cancer cells. The events shown is able to enhance the anti-tumor activity of immune reactions including spontaneous hepatocarcinomas lymphocytes infiltration and destruction of tumor tissue. As a result, the hereditary tumors incidence, their number and sizes were reduced as well as life-span and life quality of animals were improved.Conclusion.Up-regulated leukocyte integrins expression on peripheral blood cells, reduced IL-6 and IL-10 serum levels accompanied by tumors lymphocyte infiltration and destruction using MPAC preventive administration is essential for tumor incidence down-regulation. The herbal formula with multiple components is capable to controle anti-tumor immune reactions, as well as the life-span and life quality of high-cancer animals. Hence, the regulation of adhesion violations involved in tumor incidence can be cancer preventive.

Distinct recognition of complement iC3b by integrins αXβ2 and αMβ2

Recognition by the leukocyte integrins αXβ2 and αMβ2 of complement iC3b-opsonized targets is essential for effector functions including phagocytosis. The integrin-binding sites on iC3b remain incompletely characterized. Here, we describe negative-stain electron microscopy and biochemical studies of αXβ2 and αMβ2 in complex with iC3b. Despite high homology, the two integrins bind iC3b at multiple distinct sites. αXβ2 uses the αX αI domain to bind iC3b on its C3c moiety at one of two sites: a major site at the interface between macroglobulin (MG) 3 and MG4 domains, and a less frequently used site near the C345C domain. In contrast, αMβ2 uses its αI domain to bind iC3b at the thioester domain and simultaneously interacts through a region near the αM β-propeller and β2 βI domain with a region of the C3c moiety near the C345C domain. Remarkably, there is no overlap between the primary binding site of αXβ2 and the binding site of αMβ2 on iC3b. Distinctive binding sites on iC3b by integrins αXβ2 and αMβ2 may be biologically beneficial for leukocytes to more efficiently capture opsonized pathogens and to avoid subversion by pathogen factors.

Biology and structure of leukocyte β2 integrins and their role in inflammation

Integrins comprise a large family of αβ heterodimeric cell adhesion receptors that are expressed on all cells except red blood cells and that play essential roles in the regulation of cell growth and function. The leukocyte integrins, which include members of the β1, β2, β3, and β7integrin family, are critical for innate and adaptive immune responses but also can contribute to many inflammatory and autoimmune diseases when dysregulated. This review focuses on the β2integrins, the principal integrins expressed on leukocytes. We review their discovery and role in host defense, the structural basis for their ligand recognition and activation, and their potential as therapeutic targets.