Gastrin in pancreatic tumors transfected with CCK-B receptors.
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Cell Division↗
Biomedical subjects
S A Watson
Publications and source records attributed to S A Watson.
Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy.
The aim of the study was to investigate expression of the active and inactive gelatinases (MMP-2 and -9) in colorectal neoplasia and gastric cancer compared with normal mucosa. A total of 53 colorectal cancers and corresponding normal mucosa were studied using gelatin zymography as well as 15 colorectal adenomas and 13 gastric cancers with corresponding normal mucosa. Overexpression of all the gelatinases occurs in both colorectal and gastric cancer, with activation of MMP-2 appearing to be a feature of the malignant phenotype. Overexpression of MMP-9 occurs in colorectal adenomas. The gelatinases are overexpressed in gastrointestinal neoplasia, suggesting that these enzymes may have an important role in tumour invasion and metastasis.
Adenoma↗
Gastric carcinoid expresses the gastrin autocrine pathway.
BACKGROUND: In gastric adenocarcinoma the gastrin autocrine-paracrine pathway is activated. As enterochromaffin-like (ECL) cells originate from the same stem as epithelial cells, the aim of this study was to determine if the gastrin autocrine pathway is present in gastric carcinoid. METHODS: Samples from ten patients with gastric carcinoid were assessed by immunocytochemistry using primary antibodies directed against gastrin precursors and the gastrin/cholecystokinin B receptor and detected using the avidin-biotin immunoperoxidase system. RESULTS: A high level of expression of precursor and mature gastrin peptides, together with the gastrin receptor, was seen in all carcinoids screened. CONCLUSION: In common with the glandular epithelium of the stomach the gastrin gene is activated during the neoplastic process in ECL cells. This finding may explain why some carcinoids do not regress after surgical procedures that lower serum gastrin. Antigastrin agents may be a useful treatment for carcinoid either in their own right or as an adjunct to surgery.
Adult↗
Coexpression of gastrin and gastrin receptors (CCK-B and delta CCK-B) in gastrointestinal tumour cell lines.
BACKGROUND: The peptide hormone gastrin is a recognised growth factor for gastrointestinal (GI) tumour cells. Carboxyamidated gastrins bind to the cell surface gastrin/cholecystokinin B (CCK-B) receptor which can be expressed as either a normal or a truncated isoform (delta CCK-B). AIMS: To compare gastrin gene expression with delta CCK-B and total CCK-B (both isoforms) gene expression in both GI and non-GI tract derived human tumour cell lines. METHODS: Total RNA was extracted and gene expression was assayed by the reverse transcription-polymerase chain reaction followed by Southern blotting and hybridisation with specific oligo probes. RESULTS: Gastrin was expressed by 5/5 gastric and 7/8 colorectal cell lines. Coexpression of gastrin CCK-B isoform was found in 80% of gastric and 75% of colorectal cell lines. Non-GI cell lines, with the exception of a lymphoblastic leukaemia cell line, showed no coexpression. The truncated receptor, delta CCK-B, was shown in 3/5 gastric and 5/8 colorectal cell lines and was always coexpressed with gastrin. CONCLUSIONS: The truncated gastrin receptor, delta CCK-B, is coexpressed with gastrin in 8/13 GI tumour cell lines. Gastrin and CCK-B receptor isoforms may be involved in maintaining autocrine/paracrine growth pathways in GI cancer cells.
Blotting, Southern↗
Non-cytotoxic control of colorectal cancer.
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Colorectal Neoplasms↗
Phase I/II trial of batimastat, a matrix metalloproteinase inhibitor, in patients with malignant ascites.
Matrix metalloproteinases have been shown to be important in tumour invasion and metastasis, and the use of matrix metalloproteinase inhibitors in animal models has suggested that these agents may be useful in the control of malignant disease. This article reports the results of an early clinical trial of batimastat, one of the first generation of metalloproteinase inhibitors, in patients with malignant ascites. The drug was well absorbed via the intraperitoneal route and associated with few side-effects. Furthermore, a response to treatment was seen in about half the evaluable patients with advanced malignant disease. The results suggest that further research on the use of matrix metalloproteinase inhibitors in patients with malignant disease is worthwhile.
Aged↗
The effect of onapristone, a progesterone antagonist, on the growth of human gastrointestinal cancer xenografts.
Onapristone is a progesterone antagonist which inhibits the growth of mammary tumours in mice. The effect of Onapristone and concomitant oestrogen (E2) supplements on the growth of five human gastrointestinal cancer xenografts was examined. E2 stimulated RD19 (gastric tumour) tumour growth in female mice and tumours grew less well when also treated with Onapristone (P < 0.05). Onapristone had no effect on male mice bearing RD19 tumours or mice of either sex bearing MKN45G (gastric) tumours. PAN-1 (pancreatic) tumours were significantly stimulated by E2 (by 64% of control, P = 0.02) and Onapristone treatment inhibited E2 stimulated growth (52% reduction of E2 control, P > 0.05). C146 (colorectal) tumour growth was not stimulated by E2 nor inhibited by Onapristone. E2 stimulated formation of AP5LV (colorectal) tumour nodules (in lungs) (mean 38-52, P = 0.001). Onapristone significantly reduced the number of nodules (mean 32, P < 0.05) only in female mice not given E2. Xenografts of some GI tumour cell lines grow at different rates in male and female mice. E2 may cause additional growth stimulation and E2 stimulated growth can be reversed by Onapristone to basal levels.
Analysis of Variance↗
Matrix metalloproteinases.
BACKGROUND: The matrix metalloproteinases (MMPs) have a role in gastrointestinal malignancy. This role is reviewed, with particular reference to the gelatinase subgroup of enzymes. METHODS: All relevant papers derived from the Medline and Enbase databases between 1984 and early 1996 were reviewed. RESULT AND CONCLUSION: There is now strong evidence that MMPs play a major role in tumour invasion and metastasis. The development of MMP inhibitors may lead to important new treatment for the control of malignant disease.
Clinical Trials as Topic↗
Gastrimmune raises antibodies that neutralize amidated and glycine-extended gastrin-17 and inhibit the growth of colon cancer.
The effect of gastrin neutralization was evaluated on the in vivo growth of the rat colon line, DHDK12, which expressed cholecystokinin B/gastrin receptors and secreted glycine-extended gastrin-17 (G17). Gastrin neutralization was achieved by administration of the immunogen, Gastrimmune, which is composed of the amino terminal portion of G17 linked to a diphtheria toxoid. A rat-specific version of Gastrimmune was used to preimmunize rats, with control animals receiving diphtheria toxoid only. The antibodies raised neutralized both carboxy-amidated and glycine-extended G17. The tumor was implanted into the muscle layer of the abdominal wall, and rats immunized with Gastrimmune had significantly reduced median cross-sectional tumor areas (70.2% reduction; P = 0.005) and weights (56.5% reduction; P = 0.0078)) when compared to control rats. Histological analysis revealed that the tumors had an enhanced degree of necrosis, with the area of viable tumor in the Gastrimmune-immunized rat reduced to 40.3% compared to 58.6% in the control rats (P = 0.003). Immunization with Gastrimmune raised antibodies that inhibited the growth of a rat colon tumor. This could have been mediated by neutralization of both serum G17 and cell-associated precursor gastrin molecules.
Amino Acid Sequence↗
Malignant ascites.
Investigation and treatment of malignant ascites are often in the hands of the general surgeon and can be difficult. This article considers the aetiology and pathophysiology of malignant ascites and explores the best form of management. Established treatment modalities and new therapeutic options are reviewed and a new management regimen based on a knowledge of the tumour of origin is proposed, which aims to balance potential benefit against morbidity.
Abdominal Neoplasms↗
Oestrogen and progesterone receptors in gastrointestinal cancer cell lines.
Expression of sex steroid receptors by gastrointestinal (GI) tumours may indicate a role for hormonal manipulation in their management. A panel of seven established cell lines derived from primary human GI tumours were assayed for oestrogen and progesterone receptor (ER and PgR) expression by ligand binding, immunocytochemistry and enzyme-immunoassay methods. It was possible to demonstrate very low levels of both ER and PgR in the GI cell lines using enzyme immunoassay (EIA), with levels of PgR generally higher than those for ER. Neither ER nor PgR were detected in cytosols made from the GI cell lines in a classical dextran coated charcoal ligand binding assay. Similarly, immunohistological analysis (Abbott ERICA, PgRICA) of cultured cell preparations or of frozen and paraffin sections of xenograft tumour failed to demonstrate receptors. This confirms that low PgR levels are measurable by EIA in GI tumour cell lines. Upregulation of PgR expression in tumours by exposure to oestradiol in vitro was not observed.
Animals↗
Therapeutic effect of the matrix metalloproteinase inhibitor, batimastat, in a human colorectal cancer ascites model.
The matrix metalloproteinase inhibitor batimastat was administered to a human colorectal cancer ascites model, which was initiated by injection of C170HM2 cells into the peritoneal cavity of SCID mice and resulted in solid tumour deposits and ascites formation. The cell line expressed both the 72 and 92 kDa forms of gelatinase by zymography. Batimastat administered from day 0 (40 mg kg-1) reduced the volume of ascites to 21% of control in mice treated from day 0 (P < 0.002) but not day 10. Formation of solid peritoneal deposits was significantly reduced to 77% of vehicle control when batimastat was administered from day 0 (P < 0.01) and 69% of control when administered from day 10 (P < 0.05). Thus, batimastat has the ability to reduce the volume of ascites forming in SCID mice injected intraperitoneally with the human colorectal cell line, C170HM2, when administered from day 0 but not from day 10. Solid peritoneal tumour deposits were significantly reduced in both treatment groups, highlighting the therapeutic potential of batimastat in this clinical condition.
Animals↗
Effect of gastrointestinal hormones and synthetic analogues on the growth of pancreatic cancer.
The effects of hormones and synthetic analogues have been examined on the growth of 2 human pancreatic cancer cell lines, MiaPaCa2 a well-established cell line and PANI which was derived in our own laboratories from a tumour specimen. The hormones/growth factors included gastrin (G-17), epidermal growth factor (EGF) and bombesin, while the synthetic analogues used were a gastrin receptor antagonist (CR 1718), a somatostatin analogue (RC-160) and a bombesin receptor antagonist (ICI 216,140). Cell proliferation was assessed by the [75Se]selenomethionine uptake method which has been shown to correlate with cell counts. The effect of each hormone or growth factor on growth was expressed as a percentage of the untreated control. There were 5 replicates in each experiment, and each one was repeated at least 3 times. In vitro growth of both cell lines was unaffected by gastrin, bombesin or the respective antagonists (CR1718 and ICI 216140). The somatostatin analogue RC-160 also had no effect on basal growth. Significant growth stimulation of both MiaPaCa2 and PANI was seen with epidermal growth factor. We tested the hypothesis that somatostatin analogues may inhibit EGF-stimulated growth on both MiaPaCa2, a somatostatin receptor positive cell line, and on PANI which is negative for somatostatin receptors. RC-160 did not inhibit EGF-stimulated growth of either MiaPaCA2 or PANI. Both cell lines were established in vivo as xenografts in nude mice. The effect of RC-160 on tumour growth was measured. RC-160 inhibited the growth of MiaPaCa2, the somatostatin receptor-positive cell line, but not of PANI.
Adenocarcinoma↗
Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models.
The effect of the matrix metalloproteinase inhibitor batimastat was evaluated in two human colorectal cancer metastasis models involving: (a) the liver-invasive tumor C170HM2 and (b) the lung-invasive tumor AP5LV, both of which have been shown to express the M(r) 72,000 type IV collagenase. Batimastat at concentrations between 0.01 and 3.0 micrograms/ml had no direct cytotoxic effects on the in vitro growth of the cell lines. In the liver-invasive tumor model, batimastat administered i.p. from day 10 to termination of the therapy (day 39) at 40 mg/kg reduced both the mean number of liver tumors (35% of vehicle-treated control; P < 0.05) and the cross-sectional area of the tumors (43% of vehicle-treated control; P < 0.05). In the lung-invasive tumor model, batimastat administered daily (40 mg/kg i.p.) significantly reduced tumor weight within the lung (72% of vehicle-treated control; P < 0.05) but did not significantly affect nodule number. In the latter model, in which the take rate was unaffected, tumor cells were introduced into the lateral tail vein, and lung localization may have been a physical phenomenon not involving invasion. In the former model, tumor cells were introduced directly into the peritoneal cavity, and from there the cells adhered to and invaded the liver capsule. Because the take rate is significantly reduced, it may be that the matrix metalloproteinases are involved in this process. Batimastat may be a therapeutic modality for the treatment of colorectal cancer metastasis.
Animals↗
Anti-gastrin antibodies raised by gastrimmune inhibit growth of the human colorectal tumour AP5.
The neutralising ability of rabbit anti-gastrin-17 (G17) antiserum raised by Gastrimmune, an immunogen constructed of the N-terminal portion of human G17 conjugated to diptheria toxoid (DT), was evaluated. The anti-serum (denoted anti-G17: DT) was shown to displace 125[I] G17 from the gastrin receptors on AR42J cells. The therapeutic effect of the rabbit anti-G17:DT anti-serum was evaluated on a freshly derived human colorectal cancer cell line, AP5, which was shown to express both gastrin receptors and gastrin immunoreactivity as assessed by immunocytochemistry. Rabbit anti-G17:DT anti-serum was shown to block basal in vitro growth of AP5 cells when used at an antigen binding capacity of 3.75 x 10(-9) M. The same dilution of anti-serum completely reversed growth stimulated by human G17 at concentrations of 1 x 10(-10) and 1 x 10(-9) M but did not inhibit growth at 1 x 10(-8) M G17. When AP5 was grown as a xenograft in nude mice, the sensitivity to the proliferative effect of human G17 was maintained. In addition, the basal growth of AP5 xenografts was significantly reduced by i.v. infusion of rabbit anti-G17:DT anti-serum when compared to treatment with rabbit anti:DT control anti-serum. Thus anti-G17:DT antibodies raised by Gastrimmune may be of clinical value in gastrin-sensitive tumours.
3T3 Cells↗
Gastrin sensitivity of primary human colorectal cancer: the effect of gastrin receptor antagonism.
The purpose of this study was to determine the effect of the gastrin receptor antagonist, CR2093, on basal and gastrin-stimulated growth of primary human colorectal adenocarcinomas and to relate this to gastrin receptor expression. Tumour cells, derived from surgical specimens by enzymatic disaggregation, were grown on matrices of type I collagen and irradiated fibroblasts. Gastrin receptor expression was measured by using a mouse monoclonal antibody directed against the gastrin receptor and an avidin-biotin immunocytochemical method. Increased growth in the presence of gastrin-17 (used at physiological concentrations and as assessed by [3H] thymidine uptake) was shown in 16/34 (47%) tumours. CR2093 significantly reversed this stimulated growth (P < 0.05, one way analysis of variance) in 9/16 (56.3%) of the tumours and inhibited the basal growth of 11/34 (32.4%). Basal growth inhibition was reversed by gastrin-17 in 82% (9/11) of tumours. Gastrin receptor expression was widespread, but was not related to the degree of growth response to gastrin, and there was no significant correlation between intensity of receptor expression and inhibition of basal growth by CR2093. In conclusion, both gastrin-stimulated and basal growth of primary human colorectal can be inhibited by gastrin receptor antagonism, but gastrin receptor expression does not predict the sensitivity of tumours to (i) the proliferative effects of gastrin or (ii) the inhibitory effects of a gastrin receptor antagonist on basal growth. Antigastrin agents may have clinical value in the treatment of gastrin-sensitive colorectal tumours, and gastrin receptor expression may be related to endogenous gastrin production by colorectal tumour cells.
Amino Acids↗
Inhibitory effects of the gastrin receptor antagonist CR2093 on basal, gastrin-stimulated and growth factor-stimulated growth of the rat pancreatic cell line AR42J.
AR42J, a rat pancreatic cell line expressing receptors for both gastrin and epidermal growth factor (EGF), has been used to examine the effect of the gastrin receptor antagonist CR2093 on basal, gastrin-17 (G17), EGF and transforming growth factor (TGF)-alpha stimulated growth in vitro. In serum-free conditions, CR2093 reduced the basal growth of AR42J at a concentration known to displace physiological levels of G17 from gastrin receptors and this effect was reversed by G17 at 1 x 10(-9) M. Alone, G17 had little effect on growth, but EGF and TGF-alpha stimulated growth to 181 and 176% of control values, respectively, and marked synergy was observed when G17 was used in combination with both EGF (212%) and TGF-alpha (259%). When CR2093 was added, the synergistic effects of the G17/EGF and G17/TGF-alpha combinations were reduced to basal levels. In addition, CR2093 inhibited the growth stimulation induced by EGF and TGF-alpha alone. When the ability of CR2093 to bind to EGF receptors was assessed in a ligand binding assay, it was found that the antagonist displaced up to 23% of labeled EGF. Thus CR2093 has potent inhibitory effects on the basal growth of AR42J which can be reversed by G17. It can also inhibit type 1 growth factor-stimulated growth, but although this action may in part be related to the antagonist's ability to inhibit binding to the EGF receptor, other mechanisms may be involved.
Amino Acids↗
Sheep vibrissa dermal papillae induce hair follicle formation in heterotypic skin equivalents.
Cultured skin equivalents were constructed by combining keratinocytes, outer root sheath cells or isolated epidermis, in vitro, with a matrix composed of collagen and cultured fibroblasts. When equivalents were grafted on to host animals, the epidermis thickened considerably, and tongues of cells penetrated the dermis, giving the dermal/epidermal junction a deeply sculptured profile. No cutaneous appendages were found in these grafts. We explored the possibility of inducing hair follicles by incorporating ovine hair follicle dermal papillae into constructs composed of an isolated epidermal sheet and a contracted dermal equivalent. In vitro, no morphogenetic changes associated with follicle formation were observed in the recombinants, but when grafted on to nude mice, follicle-like structures were identified. The follicles were large, and had developed adjacent to the epidermis, indicating that the matrix environment of the induced follicles may not have been compatible with the downgrowth of the epidermal plugs normally observed during follicle formation in living skin. Nevertheless, in histological sections, the induced structures displayed many of the morphological characteristics of follicles in vivo, including the production of keratinized hairs. These results indicate that skin equivalents provide a useful model for the study of the chemical and structural features of matrices that facilitate hair follicle development.
Animals↗