ABSTRACT
Metastasis to bone, liver and lungs is the primary cause of death in breast cancer patients. Our studies have revealed that the novel tumor suppressor Pdcd4 inhibits breast cancer cell migration and invasion in vitro. Loss of Pdcd4 in human nonmetastatic breast cancer cells increased the expression of lysyl oxidase (LOX) mRNA. LOX is a hypoxia-inducible amine oxidase, the activity of which enhances breast cancer cell invasion in vitro and in vivo. Specific inhibition of LOX activity by beta-aminopropionitrile or small interfering RNA decreased the invasiveness of T47D and MCF7 breast cancer cells attenuated for Pdcd4 function. Most significantly, loss of Pdcd4 augments hypoxia induction of LOX as well. Conversely, overexpression of Pdcd4 significantly reversed the hypoxia induction of LOX expression in T47D cells attenuated for Pdcd4. However, Pdcd4 did not affect hypoxia-inducible factor-1 (HIF-1) protein expression or HIF-1-responsive element-luciferase activity in response to hypoxia, suggesting that Pdcd4 regulation of LOX occurs through an HIF-independent mechanism. Nevertheless, the loss of Pdcd4 early in cancer progression may have an important role in the increased sensitivity of cancer cells to hypoxia through increased LOX activity and concomitant enhanced invasiveness.
Subject(s)
Apoptosis Regulatory Proteins/metabolism , Breast Neoplasms/pathology , Protein-Lysine 6-Oxidase/metabolism , RNA-Binding Proteins/metabolism , Apoptosis Regulatory Proteins/deficiency , Apoptosis Regulatory Proteins/genetics , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Hypoxia , Cell Line, Tumor , Cell Movement/genetics , Collagen/metabolism , Drug Combinations , Gene Expression Regulation, Neoplastic/genetics , Gene Knockdown Techniques , Humans , Hypoxia-Inducible Factor 1/metabolism , Laminin/metabolism , Neoplasm Invasiveness/genetics , Protein-Lysine 6-Oxidase/genetics , Proteoglycans/metabolism , RNA-Binding Proteins/geneticsABSTRACT
The effect of abdominal rectopexy on bowel function is difficult to assess in retrospective studies because preoperative bowel habit cannot be determined accurately. This study examined bowel symptoms and physiologic tests of anorectal function prospectively in 23 patients before and at three months after rectopexy. Rectopexy eliminated complete prolapse in all and stopped bleeding in 16 of 18 patients. Incontinence improved significantly. Constipation (less than 3 bowel actions per week or straining for more than 25 percent of defecation time) was relieved in 4 of 11 affected patients but developed in 5 of the 12 who were not constipated preoperatively. Since the median bowel frequency was 21 motions per week before surgery and 17 afterward, the main determinant of constipation was straining. Abdominal pain was relieved after rectopexy in 6 of 12 patients but developed in 3 of 13 who were pain-free before surgery. Three patients (13 percent) had a first-degree relative with rectal prolapse. Perineal descent decreased significantly. Maximal anal resting pressure increased significantly, but this did not correlate significantly with improved continence. Twenty-one patients (91 percent) could expel a 50-ml balloon preoperatively; 18 of those 21 could still do so postoperatively. The two patients who could not expel the balloon preoperatively were able to do so postoperative. This study shows that rectal prolapse is associated with profoundly abnormal defecation and abdominal pain. While abdominal rectopexy improved continence, it may improve or worsen other bowel symptoms, including constipation.
Subject(s)
Anal Canal/physiopathology , Defecation , Rectal Prolapse/surgery , Rectum/physiopathology , Abdominal Pain/etiology , Abdominal Pain/prevention & control , Adolescent , Adult , Aged , Constipation/etiology , Constipation/prevention & control , Evaluation Studies as Topic , Female , Humans , Middle Aged , Postoperative Complications/prevention & control , Prospective Studies , Rectal Prolapse/physiopathology , Rectum/surgeryABSTRACT
Human gut-associated immunoregulatory events were studied in a pokeweed mitogen (PWM)-stimulated culture system using lymphocytes obtained from the mesenteric lymph nodes (MLN) of female subjects undergoing gastroplasty for obesity. Compared with peripheral blood lymphocytes, lymphocytes obtained from MLN secreted IgG, IgA and IgM isotypes that differ in pattern and distribution despite similar proportions of T cells and B cells expressing isotype-specific surface membrane immunoglobulin (SmIg). Among the isotypes secreted, IgA appeared to be increased relatively to other isotypes in MLN cultures. Crossover coculture experiments using T and B cells isolated from both MLN and blood by E-rosetting and cell panning procedures demonstrated that IgA was particularly sensitive to help and suppression exerted by MLN T cells and T cell subsets defined by monoclonal antibodies OKT4 and OKT8 respectively, when compared with similar subsets isolated from blood. The results presented provide a basis for study of gut handling of ingested antigen in man, and of disturbed immunoregulatory events in inflammatory and neoplastic disease of the human gut.
