Gastrin and colorectal cancer

The aim of present study was to assess preoperative/postoperative serum gastrin level variations and their prognostic value in patients with colo-rectal cancer. Levels have been evaluated in 66 subjects undergoing colo-rectal cancer surgery, with curative intent, from may 1990 to february 1994. Preoperative gastrin analysis was performed on peripheral blood samples in starred patient just prior surgery. Postoperative gastrin assessment was performed 7 day after surgery in starred patients as well. Follow-up ranged from 5 to 8 years. No association between preoperative gastrin levels and tumor site, stage or grading was observed. No significant variation of preoperative gastrin levels (p > 0.05) was ascertained postoperatively neither in the whole patient series nor after correction for tumor stage. Postoperative levels were therefore not affected by surgical removal of cancer. Neither preoperative nor postoperative serum gastrin levels influenced significantly the 5-year survival. In our experience, with the limitation of a small series assessment, serum gastrin level do not seem to have any prognostic value in colo-rectal cancer.     

Pentagastrin stimulates in vitro growth of normal and malignant human colon epithelial cells

Five normal and four malignant human colon epithelial cultures initiated and maintained in our laboratories as well as the standardized in vitro human adenocarcinoma cell line HT-29 were plated in multiwell plates and incubated at 37 degrees C for 72 hours with either phosphate-buffered saline solution or pentagastrin (5 micrograms/ml). Pentagastrin stimulated normal cells to increase (p less than 0.05) in number by an average of 65 percent compared with saline control cells, whereas malignant cells increased an average of 59 percent compared with control cells. There was no difference in the magnitude of trophic effect between the normal and malignant cells. Further studies are indicated to elucidate the role of gastrin in either initiating, promoting, or both, the growth of carcinoma of the colon.     

循环中胰岛素样生长因子-Ⅰ水平调节结肠癌的生长和转移研究

目的　探讨血清中肝特异性胰岛素样生长因子 Ⅰ (IGF Ⅰ )水平在刺激小鼠结肠癌生长和转移中的作用。方法　我们实验中所用的肝脏特异性IGF Ⅰ基因缺失 (LID)小鼠 ,其循环中IGF Ⅰ水平仅为正常小鼠 (对照组小鼠 )的 2 5 %。将Colon 3 8腺癌组织块 (碎片 )植入LID和对照组小鼠的盲肠表面。总共 15 6只 5周龄的雄鼠 (其中 82只LID小鼠 ,74只对照鼠 )接受了肿瘤移植。小鼠被随机分成两组 :一组接受腹腔注射重组人IGF 1(rhIGF 1) ,每天 2次 ,共 6周 ,另一组接受生理盐水注射。结果　接受rhIGF Ⅰ注射组的LID和对照小鼠 ,血清IGF 1和IGFBP 3水平均升高。在生理盐水注射组中 ,对照鼠的盲肠肿瘤的发生率和肝脏转移率显著高于LID小鼠。和盐水注射组相比 ,腹腔注射rhIGF 1组中 ,LID和对照组小鼠均有显著的盲肠癌发生率和肝脏转移率。对照小鼠的肝脏转移结节数明显高于LID鼠。结肠癌组织VEGF的表达和血管的密度依赖于血液中IGF Ⅰ水平。结论　血液循环中IGF I水平在结肠癌发展和转移中起了重要作用。     

Sulforaphane inhibits growth of a colon cancer cell line

Objective The consumption of cruciferous vegetables has a protective effect on the development of colorectal cancer. The phytochemical Sulforaphane is an isothiocyanate found almost exclusively in cruciferous vegetables. We have studied the effect of Sulforaphane on cell proliferation of an HT‐29 colon cancer cell line. Materials and methods HT‐29 colon cancer cells were cultured in 96‐well microtitre plates. Sulforaphane (in concentrations ranging from 0.01 to 0.1 mmol) were added to the wells. Cell proliferation was measured using the colourimetric assay technique. Results The proliferation of colon cancer cells was significantly reduced by Sulforaphane at concentrations of ≥0.02 mmol. Conclusion These findings may help explain the epidemiologically proven protective effect of vegetables against colon cancer.     

Interleukin-4 stimulates androgen-independent growth in LNCaP human prostate cancer cells

BACKGROUND: Clinical data showed that the levels of interleukin-4 (IL-4) are significantly elevated in serum of patients with ablation resistant prostate cancer. Previous studies demonstrated that IL-4 enhances androgen receptor (AR) activation mediated by NF-kappaB in the absence or in the very low levels of androgen in prostate cancer cells. In this study, the role of IL-4 in promoting the growth of androgen-independent prostate cancer cells was examined. METHODS: LNCaP cells were transfected with a full-length IL-4 cDNA and stable clones expressing IL-4 were selected. The growth of LNCaP cells expressing IL-4 was analyzed in vitro and in vivo both in the presence and absence of androgen. RESULTS: Overexpression of IL-4 enhances the growth of androgen-sensitive LNCaP cells in culture media containing charcoal-stripped FBS condition (CS-FBC), and increases the sensitivity of LNCaP cells in response to androgen stimulation. The DHT-mediated cell growth could not be blocked by bicalutamide in IL-4 overexpressing LNCaP cells, but can be neutralized by bicalutamide in parental LNCaP and neo control cells. Furthermore, overexpression of IL-4 stimulates tumor growth of androgen-sensitive LNCaP cells both in intact and castrated male mice. CONCLUSIONS: Overexpression of IL-4 increases the sensitivity of androgen-sensitive LNCaP prostate cancer cells in response to androgen stimulation and enhances the growth of LNCaP cells both in the presence and absence of androgen in vitro and in vivo. These studies suggest that IL-4 plays an important role in promoting androgen-independent prostate cancer growth.     

Novel anti-adhesive barrier Biobarrier reduces growth of colon cancer cells

Background

Postoperative peritoneal carcinomatosis together with adhesion formation are considered as two major clinical complications after resection of malignant abdominal tumors, jeopardizing the beneficial effect of the curative surgery. Biobarrier is a novel anti-adhesive barrier fulfilling the criteria for a good adhesion preventive agent, possessing biochemical properties that may enable it to function as a dual efficient device, reducing both adhesion and tumor development. This study aims to evaluate the effect of novel anti-adhesive device Biobarrier on intra-abdominal tumor progression.

Materials and methods

Cells from cancer cell line BN7005H1D2 were treated with Biobarrier to determine the effect of Biobarrier on cell attachment and viability in vitro. For the in vivo experiments, bilateral peritoneal trauma was inflicted in a reproducible syngeneic rat model. To mimic the clinical situation, the animals received an intraperitoneal injection of BN7005H1D2 cancer cells at the end of surgery, resembling perioperative tumor spill after intraperitoneal instillation of Biobarrier. Animals without given anti-adhesive treatment were used as control.

Results

Biobarrier applied in vitro hindered cells from attachment to the wells. In vivo treatment with Biobarrier significantly reduced tumor growth at both sites of surgical trauma (P = 0.001 and 0.015) and other non-traumatized intraperitoneal sites (P = 0.021).

Conclusions

Biobarrier maybe effective in reducing intra-abdominal tumor cell implantation with subsequent tumor development in conjunction with peritoneal trauma in a syngeneic rat model.     

Effect of morphine on growth of metastatic colon cancer in vivo

Control of colon cancer depends, in part, on intact immune defense mechanisms. Since opiates are known to affect some components of immune function, this study was conducted to determine the effect of high-dose subcutaneous morphine sulfate and of low-dose intrathecal morphine on the postoperative growth of metastatic colon cancer. Five groups of 15 Fischer 344 rats were given intraportal injections of colon cancer cells as follows: group 1, control; group 2, daily subcutaneous injections of 20-mg/kg morphine the day before and for 2 days after colon cancer cell inoculation; group 3, daily subcutaneous injections of saline; group 4, daily intrathecal injections of 20 micrograms of morphine; and group 5, daily intrathecal injections of saline. There was a significant decrease in the hepatic tumor burden in group 2 compared with groups 1 and 3 and a significant increase in the hepatic tumor burden in groups 4 and 5 compared with group 1. This study demonstrates that intermittent injections of a narcotic may decrease the growth of tumor cells that gain access to the circulation during a surgical procedure. In addition, the results support the concept that tumor cells entering the circulation during a vulnerable period of postoperative immunosuppression are more likely to survive as metastatic tumor.     

Pentagastrin stimulates potassium absorption from the rat colon.

Pentagastrin is trophic to the colon but the physiologic effects of pentagastrin are incompletely known. We compared in vivo potassium (K+) absorption from the colons of pentagastrin-treated (PG, n = 13), sham (S, n = 12), and control (C, n = 3) Sprague-Dawley rats during continuous intraluminal K+ perfusion. Preoperative intraperitoneal injections were administered to PG (pentagastrin 0.25 mg/kg in 2 mL 0.9% NaCl q 12 h x 48 h) and S (2 mL 0.9% NaCl q 12 h x 48 h). Under xylazine anesthesia, cannulae were placed in the cecum, rectum, and femoral artery of each rat. Intraluminal perfusion was performed for 2 h at 30 mL/min with 40 meq/L KCl in 0.9% NaCl (PG and S) or 0.9% NaCl (C). We monitored serum sodium (Na+) and K+ every 15 min, and the affluent and effluent Na+ and K+ every 30 min. At each interval past 60 min, we observed higher serum K+ in PG compared with S and C (P less than .002) and higher K+ in S compared with C (P less than .05). No changes in serum Na+ occurred. We conclude that pentagastrin stimulates potassium absorption from the colon.     

Clinical utility of type 1 growth factor receptor expression in colon cancer

BACKGROUND: To evaluate the expression pattern and prognostic significance of the type 1 growth factor receptor (T1GFR) family in colon carcinoma. METHODS: Tissue microarrays were constructed using 127 tumor samples and 47 metastatic lymph nodes and T1GFR family expression was determined by immunohistochemistry. Univariate and multivariate analyses examined clinicopathologic variables for prognostic significance, and the correlation between primary and lymph node expression was determined by Spearman correlation. RESULTS: Overexpression of HER-1, HER-2, HER-3, and HER-4 in tumor samples was 32%, 1%, 12%, and 37%, respectively, and 30%, 0%, 11%, and 24% in nodal samples, respectively. On multivariate analysis, positive margins, lymphatic invasion, and HER-3 expression were significant predictors of survival outcome. There was significant correlation between tumor and regional lymph node expression for the T1GFR family members. Tumor HER-3 expression was associated with lymphatic invasion and distant recurrence. CONCLUSIONS: Tumor HER-3 expression has prognostic utility in individuals with colon carcinoma. Correlation between tumor and lymph node expression of T1GFR family members suggests that tumor receptor status may guide targeted therapy selection.     

Laparoscopic colon resection for colon cancer

INTRODUCTION: Laparoscopic colon resection for cancer is as yet an unproven operation. This review article summarizes current data on the topic. METHODS: A Medline review identified articles published since 1990 summarizing patients with potentially curable colon cancer who underwent a laparoscopic-assisted colon resection. Only articles that were randomized or had a control group with historical or matched open cases were used. RESULTS: Very few prospective randomized controls exist. Several clinical trials are under way with one completed. Data thus far support some patient benefits with a laparoscopic approach. No differences in morbidity, oncologic data, or survival appear to exist. CONCLUSIONS: The results of ongoing clinical trials are still needed to further evaluate the role of laparoscopic assisted colon resection in patients with potentially curable colon cancer.     

RhoC-siRNA 对裸鼠结肠癌移植瘤的生长抑制作用

目的 探讨小干扰RNA(siRNA)载体介导抑制RhoC表达对人结肠癌裸鼠移植瘤的抑制作用.方法 将人结肠癌细胞HT-29接种于裸鼠背部皮下,成功建立裸鼠移植瘤模型;成瘤后将RhoC-siRNA注射入裸鼠移植瘤瘤体,观察RhoC-siRNA对裸鼠移植瘤生长的影响,Western blot检测瘤体中RhoC、基质金属蛋白(MMP-2)和血管内皮生长因子(VEGF)蛋白表达.结果 RhoC-siRNA对结肠癌裸鼠移植瘤的生长有明显抑制作用,瘤体体积重量明显减轻; RhoC-siRNA治疗后瘤体内VEGF和MMP-2蛋白表达明显下降.结论 通过抑制裸鼠结肠癌移植瘤中RhoC的表达,可以抑制肿瘤的生长并下调VEGF和MMP-2的表达水平.     

磷脂酶Cε1基因对结肠癌细胞生长的抑制作用

目的 观察磷脂酶Cε1(PLCE1)基因过表达对结肠癌细胞生长增殖的影响.方法 通过基因转染、0.7 g/L浓度的G418压力维持筛选出PLCE1过表达100倍以上的SW620结肠癌细胞株；通过噻唑蓝(MTT)生长曲线、克隆形成、裸鼠成瘤等实验观察PLCE1基因过表达对结肠癌细胞生长及增殖的影响.结果 PLCE1基因过表达导致结肠癌细胞生长速度减慢,实验组平板克隆吸光度(A)值为0.3225±0.0065,软琼脂克隆数为11.80 ±2.56,肿瘤质量(0.317±0.169)g,均较亲本组和对照组显著下降,差异有统计学意义(P＜0.05),提示转染PLCE1基因后细胞恶性程度降低.结论 PLCE1过表达抑制结肠癌细胞的生长,该基因可能是新的结直肠癌相关抑癌基因.     

Geriatric colon cancer

Two hundred twenty-six patients eighty years of age or older were seen over a twelve year period, and 156 underwent surgery. These patients tolerated surgery well when complications were avoided. The five year absolute survival rate was 22.4 per cent, and the corresponding age corrected figure was 53.3 per cent. On the basis of this analysis, the prognosis of elderly patients with colorectal cancer is more favorable than of the young. Considering that these patients may have an otherwise reasonable life expectancy, it seems justified to resect the colorectal cancer and to expect a rewarding survival rate.     

Bombesin stimulates growth of human gastrinoma.

BACKGROUND. We have previously reported the first establishment and characterization of a functioning human gastrinoma (PT) xenograft. Bombesin, the equivalent of the mammalian gastrin-releasing peptide, has trophic effects on normal and neoplastic tissues of the gastrointestinal tract; the effects of gut hormones on the growth of gastrinoma are not known. The purpose of this study was twofold: (1) to determine the presence of various gut peptides in PT and (2) to determine the effect of bombesin on the growth of PT xenografts. METHODS. PT tumors were examined for expression (mRNA and protein) of various gut peptides by Northern hybridization and immunohistochemistry. In addition, PT xenografts were implanted as 3 mm2 pieces bilaterally subcutaneously in athymic nude mice. Mice were divided into two groups to receive either bombesin (5 micrograms/kg) or saline administered as intraperitoneal injections every 8 hours. Tumor area was measured twice weekly until mice were sacrificed (day 28), when tumor and normal pancreas were removed, weighed, and assayed for DNA and protein content. RESULTS. Both mRNAs and peptides of gastrin and chromogranin A were present in PT tumors. Bombesin significantly stimulated growth of PT tumors from day 18 until mice were sacrificed (day 28). As expected, bombesin stimulated pancreatic growth. CONCLUSIONS. We have demonstrated for the first time that bombesin is a trophic hormone for gastrinoma. The unique cell line PT contains gastrin and chromogranin A and will be a useful model to define the biologic mechanisms controlling the growth of human gastrinomas.     

Gastrin stimulates beta-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue

It is still unclear which factors regulate pancreatic regeneration and beta-cell neogenesis and which precursor cells are involved. We evaluated the role of intravenously infused gastrin in regenerating pancreas of duct-ligated rats. The ligation of exocrine ducts draining the splenic half of the pancreas resulted in acinoductal transdifferentiation within the ligated part but not in the unligated part. We found that infusion of gastrin from day 7 to 10 postligation resulted in a doubling of the beta-cell mass in the ligated part as measured by morphometry. This increase in insulin-expressing cells was not associated with increased proliferation, hypertrophy, or reduced cell death of the beta-cells. Furthermore, we found an increased percentage of single, extra-insular beta-cells and small beta-cell clusters induced by gastrin infusion. These changes occurred only in the ligated part of the pancreas, where transdifferentiation of the exocrine acinar cells to ductlike cells (metaplasia) had occurred, and was not found in the normal unaffected pancreatic tissue. In conclusion, we demonstrate that administration of gastrin stimulates beta-cell neogenesis and expansion of the beta-cell mass from transdifferentiated exocrine pancreas.     

胃泌素促进胃癌细胞增殖和血管生成拟态形成

目的 探讨胃泌素对胃癌细胞血管生成拟态(VM)的作用及其分子机制.方法 应用免疫细胞化学检测SGC-7901、AGS细胞中胃泌素受体(CCK-BR);用终质量浓度为10、100 nmol/L胃泌素处理SGC-7901和AGS 72 h,噻唑蓝(MTT)比色法检测细胞增殖率、实时定量聚合酶链反应(Real-time PCR)检测缺氧诱导因子-1α(HIF-1α)的表达、酶联免疫吸附实验检测血管内皮细胞生长因子(VEGF)的分泌水平;三维培养SGC-7901和AGS,用10、100 nmol/L胃泌素处理,显微镜下观察24、48、72 h VM形成,计数72 h VM形成数;软琼脂克隆形成实验检测细胞培养3周的克隆形成率.结果 SGC-7901和AGS细胞表达CCK-BR;经10、100 nmol/L的胃泌素处理后,SGC-7901和AGS的细胞增殖率和克隆形成率高于对照组,细胞的环形、半环形VM形成数也高于对照组(P＜0.01);细胞中HIF-1α的表达量比对照组上调了5.39、11.00(SGC-7901)、4.12和6.06倍(AGS);分泌性VEGF的浓度也比对照组增高[298、339 μg/mg蛋白(SGC-7901)及168和281 μg/mg蛋白(AGS),p＜0.01].结论 通过胃泌素-CCK-BR-HIF-1 α-VEGF构成的信号传递链,胃泌素促进胃癌细胞的体外增殖及VM的形成.