Bone health and maintenance of bone integrity are important components of comprehensive cancer care in both early and late stages of disease. Risk factors for osteoporosis are increased in patients with cancer, including women with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors for breast cancer, men receiving androgen-deprivation therapy for prostate cancer, and patients undergoing glucocorticoid therapy. The skeleton is a common site of metastatic cancer recurrence, and skeletal-related events are the cause of significant morbidity. The National Comprehensive Cancer Network (NCCN) convened a multidisciplinary task force on Bone Health in Cancer Care to discuss the progress made in identifying effective screening and therapeutic options for management of treatment-related bone loss; understanding the factors that result in bone metastases; managing skeletal metastases; and evolving strategies to reduce bone recurrences. This report summarizes presentations made at the meeting.
Although memory T cells respond more vigorously to stimulation and they are more sensitive to low doses of antigen than naive T cells, the molecular basis of this increased sensitivity remains unclear. We have previously shown that the T cell receptor (TCR) exists as different-sized oligomers on the surface of resting T cells and that large oligomers are preferentially activated in response to low antigen doses. Through biochemistry and electron microscopy, we now showed that previously stimulated and memory T cells have more and larger TCR oligomers at the cell surface than their naive counterparts. Reconstitution of cells and mice with a point mutant of the CD3ζ subunit, which impairs TCR oligomer formation, demonstrated that the increased size of TCR oligomers was directly responsible for the increased sensitivity of antigen-experienced T cells. Thus, we propose that an "avidity maturation" mechanism underlies T cell antigenic memory.
Heterotrimeric G proteins regulate diverse cellular responses by coupling heptahelical receptors to intracellular effectors (11,25,35). Of the different ␣-subunits that have been analyzed thus far, the ␣-subunit of the heterotrimeric G protein G12 (G␣ 12 ) shows the most potent mitogenic and oncogenic activities (5, 35). The initial identification of G␣ 12 as the transforming oncogene in Ewing's sarcoma cell lines indicated the critical role of G␣ 12 in oncogenic signaling (5). Consistent with these observations, serum stimulation or mutational activation of G␣ 12 has been shown to stimulate mitogenic pathways in different cell types in addition to inducing neoplastic transformation of 35). NIH 3T3 cells transformed by the GTPase-deficient activated mutant of G␣ 12 (G␣ 12 Q229L, or G␣ 12 QL) show the characteristic oncogenic phenotype defined by the increased proliferation, anchorage-independent growth, reduced growth factor dependency, attenuation of apoptotic signals, and neoplastic cytoskeletal changes (35). Previously, we have shown that the neoplastic growth of NIH 3T3 cells mediated by the activated mutant G␣ 12 involves the expression several unique genes, including platelet-derived growth factor receptor ␣ (PDGFR␣) (25). This finding is of critical interest since the signaling pathways involving PDGFR have been strongly correlated with cell proliferation and neoplastic transformation (18), thus pointing to a possible role of PDGFR␣ in G␣ 12 QL-mediated oncogenic signaling pathways.The receptor kinases PDGFR␣ and PDGFR are activated by dimers of PDGF isoforms, PDGF-A, PDGF-B, PDGF-C, and PDGF-D (18). Distinct homo-or heterodimers of PDGFs activate specific homo-or heterodimers of PDGFR␣ and PDGFR in a tissue-specific and context-specific manner (18). The activation of PDGFRs, leading to their dimerization and transphosphorylation at specific tyrosine residues, provides docking sites for different effector molecules such as Shp, phospholipase C-gamma, and phosphatidylinositol 3-kinase (PI3K) (18). Overexpression of PDGFR␣ or PDGFR and the associated autocrine signaling pathways appear to play an etiological role in tumorigenesis and tumorangiogenesis of different neoplasms including basal cell carcinoma (45), gastrointestinal stromal tumors (17), and ovarian cancers (19,30). It has also been observed that PDGFR, specifically PDGFR, is transactivated by G protein-coupled receptors (GPCRs) stimulated by lysophosphatidic acid (LPA) (20), sphingosine-1 phosphate (2), serotonin (33), and angiotensin II (39). However, the underlying signaling mechanisms and the role of the specific G proteins in mediating such transactivation are not fully understood.In the present study, we demonstrate that G␣ 12 QL stimulates the expression and transactivation of PDGFR␣ in NIH 3T3 cells. The ability of transiently expressed G␣ 12 QL to stimulate the expression of PDGFR␣ in 1321N1 astrocytoma cells indicates that such a nexus between G␣ 12 and PDGFR␣ is not restricted to one specific cell type. Our results indicate that...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.