Adipose Tissue Is Sensitive to Irradiation
Radiation therapy targets cancer lesions but also damages normal tissues, resulting in acute loss of rapidly dividing cells and chronic depletion of tissue-specific stem cells. Autologous transplant of tissues such as fat tissue, which is thought to be poorly proliferative and thus minimally damaged by irradiation, has often been used to prevent the fibrosis, organ dysfunction, and necrosis that result from radiation treatment. Poglio et al (Am J Pathol 2009, 174:44–53), therefore, characterized subcutaneous adipose tissue isolated from mice after total body irradiation. Surprisingly, inguinal fat pads weighed significantly less after irradiation and exhibited altered morphology, including decreased adipocyte size and reduced number of mature adipocytes. Poglio and colleagues also observed severely decreased numbers of proliferating cells and increased numbers of apoptotic cells in both hematopoietic and nonhematopoietic populations. In addition, radiation impaired both the number of progenitors and their ability to differentiate into adipocytes. These results thus call into question the effectiveness of transplanting adipose tissue during radiation therapy.
CXCL1 Decreases the Severity of Experimental Autoimmune Encephalitis
Myelin-producing oligodendrocytes in the central nervous system are severely depleted in multiple sclerosis lesions. These cells express immune receptors, including CXCR2, and have been shown to proliferate and migrate in response to a CXCR2 ligand, the chemokine CXCL1. Omari et al (Am J Pathol 2009, 174:164–176) examined the effects of inducible astrocyte-specific overexpression of CXCL1 on oligodendrocytes in experimental autoimmune encephalitis, a mouse model of multiple sclerosis. They observed decreased severity of pathology (Wallerian degeneration, demyelination) and more prominent remyelination in these mice. CXCL1/CXCR2 signaling, therefore, plays a neuroprotective role in central nervous system autoimmune demyelination.
Annexin A1 Modulates Inflammation
Annexin A1 (AnxA1) signaling plays a protective role in inflammation, with notable anti-migratory effects on neutrophils. As such, mice deficient in AnxA1 are prone to both chronic and acute inflammatory conditions. Gastardelo et al (Am J Pathol 2009, 174:177–183) investigated the identities of the receptors responsible for the anti-inflammatory effects of AnxA1 in the carrageenin-induced model of mouse peritonitis. They found that AnxA1 gene promoter activity was rapidly increased in extravasated polymorphonuclear neutrophils in carrageenin-induced peritonitis. As receptor for formylated peptides (FPR) family members had been previously shown to interact with AnxA1, Gastardelo et al then examined FPR-1-deficient mice. FPR-1-deficient mice, unlike AnxA1-null mice, did not have increased polymorphonuclear neutrophil recruitment. Instead, AnxA1 co-localized on neutrophils with another FPR family member, FPR-2. FPR-2, therefore, may serve as a new therapeutic target to mimic the anti-migratory effects of AnxA1.
Laminin-111 Therapy for Congenital α7 Integrin Myopathy
Mutations in the α7 integrin gene lead to neuromuscular defects resulting in delayed developmental milestones and impaired mobility. To determine whether α7β1 integrin is critical for muscle repair, Rooney et al (Am J Pathol 2009, 174:256–264) examined cardiotoxin-induced damage in the tibialis anterior muscle of α7 integrin-null mice. Indeed, α7 integrin-deficient muscle exhibited defective muscular regeneration when compared with wild-type controls. Rooney and colleagues injected laminin-111, a component of the basal lamina that surrounds muscle fibers, into the tibialis anterior muscle 3 days before cardiotoxin-induced injury. Laminin-111 injection restored myogenic repair and muscle regeneration in α7 integrin-deficient mice to wild-type levels. These results identify laminin-111 as a possible therapeutic target for treatment of congenital myopathies.
Cyclophilin B Expression and Regulation in Breast Cancer
Cyclophilin B (CypB) is both a transcriptional activator of signal transducer and activator of transcription 5 (Stat5)-mediated gene expression and a ligand for the cell surface receptor CD147, which regulates downstream mitogen activated protein kinase (MAPK) activation, motility, calcium transport, and the expression of the pro-apoptotic protein Bim. Fang et al (Am J Pathol 2009, 174:297–308) explored the role of CypB in the regulation of breast cancer by inhibiting CypB expression in the breast cancer cell line T47D. Microarray data showed that CypB knockdown had far-reaching effects, impacting 27 different protein networks. Many gene products regulated by CypB contribute to cell proliferation, cell motility, and tumorigenesis. Consistent with these data, CypB knockdown also decreased T47D cell growth, proliferation, and motility. In a breast tissue microarray, increases in CypB protein levels correlated with the presence of breast cancer metastases. Therefore, CypB gene regulation may contribute to the progression of breast cancer.
Inflammation-Associated Colon Cancer
Bacteria contribute to the development of certain cancers, in some measure, by stimulating chronic inflammation. Absence of the signaling molecule Smad3, which is activated in response to the inhibitory cytokine transforming growth factor (TGF-β), may therefore increase susceptibility to colon cancer. To examine whether lymphocyte TGF-β signaling contributes to development of colon cancer, Maggio-Price et al (Am J Pathol 2009, 174: 317–329) examined Smad3- and Rag2-deficient mice, which lack both adaptive immune responses and normal TGF-β signaling. They found that these mice are acutely sensitive to bacterially-induced inflammation and cancer attributable to both deficient T-regulatory cell function and increased expression of proinflammatory cytokines. Through increased expression of both pro-oncogenic and anti-apoptotic proteins, the epithelial cells in colonic tissues underwent enhanced proliferation and survival. These data suggest that the inflammatory response to microorganisms, as controlled by T-regulatory cells, plays a key role in the pathogenesis of colon cancer.