The receptor tyrosine kinase Axl has been implicated in the malignancy of different types of cancer. Emerging evidence of Axl upregulation in numerous cancers, as well as reports demonstrating that its inhibition blocks tumor formation in animal models, highlight the importance of Axl as a new potential therapeutic target. Furthermore, recent data demonstrate that Axl plays a pivotal role in resistance to chemotherapeutic regimens. In this review we discuss the functions of Axl and its regulation and role in cancer development, resistance to therapy, and its importance as a potential drug target, focusing on acute myeloid leukemia, breast, prostate and non-small cell lung cancers. Tyrosine KinasesTyrosine kinases (TKs), proteins that represent a major portion of all oncoproteins, are essential mediators of the signal transduction process and play essential roles in cell differentiation, migration, proliferation, apoptosis and metabolism. TKs are a class of enzymes which selectively catalyze phosphorylation of selected tyrosine residues in target proteins using ATP. This post-translational modification is a critical component for normal cellular communication and homeostasis and it is associated with several steps of development and progression of cancers.
Human mammary epithelial cells secrete and express on their cell surfaces complex mucin glycoproteins (Mr > 250,000) that are developmentally regulated, tumorassociated, and highly immunogenic. Studies using monoclonal antibodies directed to these glycoproteins suggest that their molecular structures can vary with differentiation stages in the normal gland and in malignancy. To analyze the molecular nature of these glycoproteins, milk mucin was affinity-purified and deglycosylated with hydrogen fluoride, yielding bands at 68 and 72 kDa on silver-stained gels. Polyclonal and monoclonal antibodies to the stripped core protein were developed and used to screen a Xgtll expression library of cDNA made from mRNA of the mammary tumor cell line MCF-7. Seven crossreacting clones were isolated, with inserts 0.1-1.8 kilobases long. RNA blot analysis, using as a probe the 1.8-kilobase insert subcloned in plasmid pUC8 (pMUC10), revealed transcripts of 4.7 and 6.4 kilobases in MCF-7 and T47D mammary tumor cells, whereas normal mammary epithelial cells from pooled milks have additional transcripts. The expression of mRNA correlates with antigen expression as determined by binding of two previously characterized anti-mucin monoclonal antibodies (HMFG-1 and HMFG-2) to seven cell lines. Restriction enzyme analysis detected a restriction fragment length polymorphism when human genomic DNA was digested with EcoRI or Hinfl.Normal and malignant human mammary epithelial cells express high molecular weight glycoproteins that are extensively glycosylated and very antigenic. As a result, many of the monoclonal antibodies (mAbs) selected for reactivity with human breast cancers are found to react with these components (1-7). These antibodies generally also react with molecules that are produced in abundance by the fully differentiated human mammary tissue and that are found in the milk fat globule and in milk. However, the level of expression of a particular antigenic determinant may be different in the glycoproteins produced by the normal differentiated cell and in the immunogenically related molecules produced by breast cancers (1,(6)(7)(8)(9). This means that some antibodies can show a certain specificity for reacting with the tumor glycoproteins, although this is quantitative rather than qualitative. The molecules expressing the epitopes recognized by these antibodies have been difficult to analyze, both because they are large (>250 kDa) and heavily glycosylated and because of their complex pattern of expression. Use of two mAbs, HMFG-1 and HMFG-2 (originally called 1.10.F3 and 14.A.3, respectively; ref. 10), has shown that the reactive component in human milk appears to be >400 kDa, while the molecules carrying the antigenic determinants in sera and tumors are smaller [but generally still >200 kDa (1)] and exhibit a genetic polymorphism (11).The large glycoprotein produced by the differentiated mammary epithelial cells and found in human milk or in the milk fat globule has been purified and shown to have features characteris...
We undertook a prospective randomised controlled trial involving 400 patients with a displaced intracapsular fracture of the hip to determine whether there was any difference in outcome between treatment with a cemented Thompson hemiarthroplasty and an uncemented Austin-Moore prosthesis. The surviving patients were followed up for between two and five years by a nurse blinded to the type of prosthesis used. The mean age of the patients was 83 years (61 to 104) and 308 (77%) were women. The degree of residual pain was less in those treated with a cemented prosthesis (p < 0.0001) three months after surgery. Regaining mobility was better in those treated with a cemented implant (p = 0.005) at six months after operation. No statistically significant difference was found between the two groups with regard to mortality, implant-related complications, re-operations or post-operative medical complications. The use of a cemented Thompson hemiarthroplasty resulted in less pain and less deterioration in mobility than an uncemented Austin-Moore prosthesis with no increase in complications.
SummaryTbx2 is a member of the T-box family of transcription factors that are crucial in embryonic development. Recent studies suggest that T-box factors may also play a role in controlling cell cycle progression and in the genesis of cancer. Tbx2 has been implicated in several developmental processes such as coordinating cell fate, patterning and morphogenesis of a wide range of tissues and organs including limbs, kidneys, lungs, mammary glands, heart, and craniofacial structures. Importantly, Tbx2 is overexpressed in several cancers including melanoma, small cell lung carcinoma, breast, pancreatic, liver, and bladder cancers and can suppress senescence, a cellular process, which serves as a barrier to cancer development. This review presents a state of the art overview of the role and regulation of Tbx2 in early embryonic development and in cancer.
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