Biomedical subjects

J E Price

Publications and source records attributed to J E Price.

At least 19 recordsLinked to original sources

PubMed1992

Basement membrane collagen-IV synthesis in colorectal tumours.

Many studies suggest that increased proteolysis accounts for the epithelial basement membrane (EBM) breaks commonly seen in carcinomas. As failure to produce or maintain EBM may also be important, we chose to investigate synthesis of basement membrane collagen-IV in human colorectal carcinomas. First, to determine the cellular origin of EBM collagen-IV, species-specific antibodies were used to analyse caecal xenografts of 4 different human colorectal-carcinoma-derived cell lines. The results of this study suggest an exclusively stromal cell origin for EBM collagen-IV. Next, the distribution of periglandular myofibroblasts in carcinomas was examined, since in normal mucosa their location and ultrastructural features suggest that they play a role in EBM maintenance. They were generally abundant in normal mucosa and adenomas, but sparsely distributed in carcinomas, particularly at the invasive periphery where EBM collagen-IV immunostaining is most deficient. Finally, the in situ hybridization technique was used to define cell populations synthesizing collagen-IV. In normal mucosa, no collagen-IV mRNA was detected in any component, while in carcinomas, the mRNA was clearly detectable in vascular endothelial cells but not in any other cell type. Increased vascular collagen-IV production in carcinomas may be at least partly due to tumour-induced angiogenesis, since new blood-vessel formation requires the synthesis of new vascular basement membranes.

Adenoma↗

PubMed1992

Gastroesophageal pH step-up inaccurately locates proximal border of lower esophageal sphincter.

Limiting the widespread use of 24-hr pH monitoring is the necessity of manometrically placing the pH probe 5 cm above the proximal lower esophageal sphincter (LES) border. Therefore, we prospectively compared LES localization by gastroesophageal pH step-up with manometry in 71 patients and 14 asymptomatic volunteers. The gastroesophageal pH step-up significantly correlated with the proximal LES border in patients (r = 0.53, P less than 0.0001) and volunteers (r = 0.91, P less than 0.0001). Based on previously published criteria, the pH step-up value was considered acceptably accurate if it was within +/- 3 cm (6 cm total span) of the manometrically determined proximal LES border. In 58% of patients and 29% of volunteers the pH step-up occurred outside this accuracy range. Esophagitis (P = 0.015) and abnormal reflux parameters (P = 0.002) were variables contributing to this error. Subsequent analysis found that the pH step-up overestimated the proximal LES border and occurred at the midportion of the sphincter. The pH step-up still inaccurately located the mid LES in 34% of patients. Therefore, manometry should remain the standard for accurate LES localization prior to placing the pH probe.

Adolescent↗

PubMed1992

Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice.

This study clarified whether and when the blood-brain barrier in experimental brain metastases is impaired by using hydrosoluble sodium fluorescein (MW 376) as a blood-brain barrier function indicator. Cells from eight human tumor lines (four melanomas, two breast carcinomas, one colon carcinoma, and one renal carcinoma) were inoculated into the internal carotid artery of nude mice. Brain metastases at different stages of development were sampled and the permeability of the blood-brain barrier around the metastases determined. Histologic examination showed two patterns of tumor growth. In the first, tumor cells formed isolated, well-defined nodules in the parenchyma of the brain. In lesions smaller than 0.2 mm2, the blood-brain barrier was intact. In the second, small diffuse nests of tumor cells were distributed throughout the brain parenchyma. The blood-brain barrier was intact until the small tumor cell colonies coalesced to form large tumor masses. These results suggest that the permeability of the blood-brain barrier varies among different experimental brain metastases and that its function is related to the growth pattern and size of the lesions.

Animals↗

PubMed1992

The LES locator: accurate placement of an electrode for 24-hour pH measurement with a combined solid state pressure transducer.

Twenty-four-hour esophageal pH monitoring is the gold standard for diagnosing gastroesophageal reflux disease. A possible limitation to the widespread use of this test is that manometry is required for accurate placement of the pH electrode 5 cm above the lower esophageal sphincter. We compared the accuracy of a single solid state pressure transducer, combined with a pH electrode, in determining the proximal border of the lower esophageal sphincter (LES) with the values obtained from stationary manometry in 40 patients referred to our laboratory for 24-h pH studies. Not only was there a strong correlation (r = 0.9) between LES values obtained by the two techniques, but none of the values obtained by the single solid state transducer were outside the clinically accepted range of greater than +/- 3 cm. The presence of a hiatal hernia or low sphincter pressure did not affect these measurements. The larger probe was tolerated somewhat less well (p = 0.02) than a standard antimony electrode during the prolonged pH studies. In conclusion, a single solid state pressure transducer on a pH probe with the help of a LES locator accurately identifies the proximal border of the LES. Therefore, stationary esophageal manometry is no longer needed prior to 24-h pH monitoring, potentially making this important clinical tool available to a wider variety of clinicians at all levels of the health care system, in investigating gastroesophageal reflux and its protean clinical presentations.

Adult↗

PubMed1991

Malignant potential of cells isolated from lymph node or brain metastases of melanoma patients and implications for prognosis.

We studied the correlation between the formation of brain metastasis and the malignant growth potential of seven human melanoma cell lines, isolated from lymph node metastases (A375-SM, TXM-1, DM-4) or from brain metastases (TXM-13, TXM-18, TXM-34, TXM-40), and the potential of three variants of the mouse K-1735 melanoma. Growth rates in different concentrations of fetal bovine serum and colony-forming efficiency in semisolid agarose were measured, and the tumorigenicity and metastatic ability were determined in nude mice (for the human melanoma cell lines) or in C3H/HeN mice (for the K-1735 variants). The ability to form brain metastasis was tested by injection of cells into the carotid artery. A high colony-forming efficiency in agarose, especially at concentrations of agarose greater than 0.6%, corresponded with high tumor take rates, rapid tumor growth rates, and metastatic colonization of the lungs of the recipient mice. For the human melanomas, the lymph node metastasis-derived cells were more tumorigenic and metastatic than the brain metastasis-derived cells. In the K-1735 mouse melanoma, the tumorigenic and metastatic behavior of the cells after i.v. and s.c. injection corresponded with growth in agarose cultures. However, for growth in the brain after intracarotid injection, the different melanoma cell lines showed similar frequencies of tumor take, regardless of tumorigenicity in other sites of the recipient mice, although mice given injections of brain metastasis-derived cells survived longer than mice given injections of lymph node metastasis (human melanoma) or lung metastasis (K-1735 M-2)-derived cell lines. The results from the human and mouse melanoma cell lines show that the brain metastasis-derived cell lines were not more malignant than the lymph node or lung metastasis-derived cells. These data imply that the production of brain metastasis is not always the final stage of a metastatic cascade.

Animals↗

PubMed1991

Growth modulation by epidermal growth factor (EGF) in human colonic carcinoma cells: constitutive expression of the human EGF gene.

The functional role of epidermal growth factor (EGF) in epithelium-derived human colonic carcinoma cells was investigated by transfection with plasmid pUCDS3, which contained synthetic human EGF encoding sequences, into two human colonic carcinoma cell types with dissimilar phenotypic properties: the moderately differentiated and growth factor-responsive Moser and the highly metastatic KM12SM cells. The Moser cells exhibited a proliferative response to treatment with exogenous EGF, while the KM12SM cells did not. The constitutive expression of the human EGF gene in these colonic carcinoma cell types resulted in elevated expression of EGF mRNA, with concurrent production and secretion of a large amount of EGF, and downmodulation of transforming growth factor-alpha (TGF-alpha) secretion. Growth stimulation and down-modulation of both high and low affinity EGF receptors were observed in the EGF-transfected Moser clones. Results of experiments using anti-EGF and anti-EGF-receptor antibody to block the proliferation of EGF-transfected Moser clones suggested that autocrine stimulatory mechanisms involving both EGF and TGF-alpha were operative in these cells. By comparison, a growth-inhibitory effect, with no apparent EGF receptor modulation, was observed in the EGF-transfected KM12SM clones. Both the parental and EGF-transfected KM12SM clones possessed fewer EGF receptors than the Moser cells, and anti-EGF or anti-EGF-receptor antibody did not affect the cells' growth properties. These results suggested that the mechanisms of growth inhibition in the EGF-transfected KM12SM clones were non-autocrine or intracellular in nature. Thus, constitutive expression of the human EGF gene in two phenotypically different, epithelium-derived human colonic carcinoma cells resulted in divergent altered growth characteristics.

Cell Division↗

PubMed1991

In vitro platelet aggregability studies: lack of evidence for platelet hyperactivity in systemic sclerosis.

Systemic sclerosis is characterised by vascular endothelial damage. Platelets adhering to the exposed subendothelium may contribute to the inflammatory changes found in the vessel wall. Increased in vitro platelet aggregability in systemic sclerosis has been reported. In vitro platelet aggregation of platelet rich plasma obtained from patients with systemic sclerosis (CREST (calcinosis, Raynaud's phenomenon oesophageal dysmotility, sclerodactyly, telangiectasia) variant) and from controls matched for age and sex was compared. Collagen, ADP, and platelet activating factor were used as aggregating agents. The actions of a platelet activating factor antagonist, BN52063, were also examined. Each agonist caused dose dependent platelet aggregation; there was no difference in either rate of primary aggregation or maximum percentage aggregation between platelets derived from patients with systemic sclerosis and from the control group (analysis of variance). BN52063 was shown to be a dose dependent, competitive antagonist of platelet aggregation induced by platelet activating factor; there was no difference in its action on platelets derived from patients with systemic sclerosis or controls. These results do not support the hypothesis that platelets from patients with systemic sclerosis are hyperactive and may explain the disappointing results obtained with antiplatelet drugs in systemic sclerosis.

Adenosine Diphosphate↗

PubMed1991

Relative malignant potential of human breast carcinoma cell lines established from pleural effusions and a brain metastasis.

Three human breast cancer cell lines from pleural effusions (MDA-MB-435, MDA-MB-231, MDA-MB-468) and one from a brain metastasis (MDA-MB-361) were tested for growth potential in vitro (minimum serum requirements, growth in semisolid agarose), for tumorigenicity and metastasis in nude mice following injection into the mammary fatpad (m.f.p.) and intravenously (i.v.), and for formation of experimental brain metastasis following injection into the carotid artery (i.a.). Colony-forming efficiency of the breast cancer cells in dense agarose corresponded with metastatic potential of the m.f.p. tumors. The results consistently ranked the 4 cell lines as follows: MDA-MB-435 greater than MDA-MB-231 greater than MDA-MB-468 greater than MDA-MB-361, from the most to the least aggressive. The exception was for tumor growth in the brain after i.a. injection of cells, where MDA-MB-361 cells were ranked as second highest for tumor take, but with the slowest growth rate. These results indicate that in this series of breast carcinomas, the cells from a brain metastasis (MDA-MB-361) have a lower malignant potential than cells from visceral metastases.

Animals↗

PubMed1990

The biology of metastatic breast cancer.

Early detection and surgical removal of breast cancer are most effective in managing a disease that may affect up to one in ten women in North America and Western Europe. However, one of the most important prognostic indicators for breast cancer is the presence of neoplastic cells in the axillary lymph nodes. The dissemination of cells from a primary lesion, resulting in the progressive growth of metastatic carcinoma in distant sites (including bone, lungs, liver, and brain) is the most common cause of death in breast cancer patients. Experimental studies on the biology of metastatic breast cancer have used rodent tumor systems, and, in recent years, the transplantation of human breast carcinoma cells into athymic mice. The results of such studies, combined with clinical observations, suggest that metastasis is not a random event. The formation of secondary lesions is the result of a sequence of selective events. A better understanding of the metastatic phenotype from cellular and molecular analyses will provide a basis for rational approaches to preventing and treating this most lethal aspect of breast cancer.

Animals↗

PubMed1990

Immune response to progressor variants derived from transfection of an ultraviolet radiation-induced C3H mouse regressor tumor cell line with activated Harvey-ras oncogene.

Skin cancers induced in mice by UV radiation often exhibit a regressor phenotype. In order to determine how tumors escape the immune defenses of the normal immunocompetent host, we sought to isolate progressor variants from a UV radiation-induced C3H mouse regressor fibrosarcoma cell line, UV-2240, by transfection with an activated Ha-ras oncogene. A cotransfection protocol using pSV2-neo DNA, which confers resistance to the antibiotic G418, was used to select transfected cells. Injection of Ha-ras-transfected UV-2240 cells s.c. into immunocompetent C3H mice produced tumors in four of 36 animals. In contrast, UV-2240 cells transfected with pSV2-neo DNA alone or mock transfected with CaPO4 did not produce tumors in normal C3H mice. DNAs from cell lines established from Ha-ras-induced tumors contained unique Ha-ras sequences in addition to those sequences endogenous to UV-2240 cells. However, the Ha-ras-induced progressor variants did not overexpress the Mr 21,000 protein. The Ha-ra-induced progressor variants produced experimental lung metastasis in both normal C3H and nude mice, although they induced more lung nodules in nude mice than in normal C3H mice. In addition, all four Ha-ras-induced progressor variants produced significantly more experimental lung metastases in nude mice than did the parent UV-2240 cell line. However, both the parental UV-2240 cell line and the Ha-ras-induced progressor variants expressed similar levels of H-2Kk and H-2Dk antigens and were immunologically cross-reactive, as determined by in vitro cytotoxic T-lymphocyte and in vivo immunization-challenge assays. These results indicate that the progressor phenotype of the Ha-ras-induced tumor variants is not due to loss of tumor-specific transplantation or Class I major histocompatibility complex antigens. This implies that some tumor cells can escape the immune defenses of the normal immunocompetent host by mechanisms other than loss of tumor-specific transplantation and Class I major histocompatibility antigens.

Animals↗

PubMed1990

The use of a genotypic marker to demonstrate clonal dominance during the growth and metastasis of a human breast carcinoma in nude mice.

When a mixture of 11 clones of a human breast carcinoma (MDA-MB-435)--each clone transfected with pSV2neo and identified as having a unique insertion site of the gene--was injected into nude mice, the resulting tumors were found to contain only one clone (Neo 24). This clone, identified by the unique restriction fragments on Southern blot analyses, was also found in metastases recovered from the lungs and lymph nodes of the animals. The individual clones showed no differences in in vitro growth, while in vivo the Neo 24 cells produced the largest tumors. Thus, one explanation for the observed clonal dominance in this study could be the more rapid growth in vivo of the Neo 24 cells. This study illustrates how an introduced selectable gene marker can be used in lineage studies of human tumor cell populations.

Animals↗

PubMed1990

Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice.

There are few reports describing experimental models of the growth and metastasis of human breast carcinomas. This article discusses the tumorigenic and metastatic properties of two estrogen receptor-negative breast carcinomas injected into nude mice. Tumor growth in the mammary fatpad (m.f.p.) and the subcutis was compared in female nude mice. The injection of 10(5) viable cells of two human breast carcinoma cell lines (MDA-MB-231 and MDA-MB-435) gave a 100% tumor take rate in the m.f.p., whereas only 40% of the s.c. injections produced tumors and these occurred several weeks after the appearance of the m.f.p. tumors. Thus, the m.f.p. of nude mice is a favorable site for the growth of human breast carcinomas. MDA-MB-435 tumors produced distant metastases in 80% to 100% of recipients. The most common sites for metastasis were the lymph nodes and lungs, with a lower incidence of metastases in muscle (chest wall and thigh), heart, and brain. New variant cell lines were isolated from metastases in the lungs, brain, and heart. All the cell lines were tumorigenic in the m.f.p., and the lung- and heart-derived metastasis lines produced slightly more lung metastases than the original cell line. However, the brain metastasis variant produced significantly fewer lung metastases. Intravenous inoculation of the spontaneous metastasis-derived cell lines produced few lung colonies. Only cell variants isolated from experimental lung metastases showed enhanced lung colonization potential when reinjected i.v. Our results suggest that the estrogen receptor-negative MDA-MB-435 cell line injected in the m.f.p. of nude mice could be a valuable tool for analysis of the cellular and molecular basis of the metastasis of advanced breast cancer.

Animals↗

PubMed1990

Studies of human breast cancer metastasis using nude mice.

Athymic nude mice have been used in recent years to study the biology of human tumors and to assess therapeutic responses in vivo rather than just in vitro. Some human tumors metastasize in nude mice, providing model systems for analyzing various aspects of the metastatic phenotype of human neoplasms. For breast carcinomas, however, the tumor-take rate of surgical specimens is low, and only a limited number of cell lines proliferate in nude mice. The site of injection of the breast carcinoma cells is important; tumors grow at a lower inoculum dose and with shorter latent intervals after implantation in the mammary fatpad of nude mice than after injection in the subcutis. One breast carcinoma cell line, MDA-MB-435, metastasizes from mammary fatpad tumors to lymph nodes, lungs, and other visceral organs. In contrast, two other cell lines show lower metastatic ability. Intravenous injection and injection of tumor cells into the internal carotid artery of nude mice produces lung and brain metastases, respectively, thus simulating the arrest and organ colonizing steps of the metastatic cascade. These different techniques demonstrate the potential of experimental studies of human breast cancer growth and metastasis using nude mice.

Animals↗

PubMed1990

The biology of cancer metastasis.

The formation of a metastasis entails a complex sequence of events with the end result dependent on the interaction of malignant cells with host factors. Intrinsic properties of the metastatic tumor cells, including production of proteolytic enzymes, cell surface properties, adhesiveness, and the ability to grow in a distant organ environment, act in concert to influence the tumor cells' interactions with host cells in forming metastases. Life-threatening metastases are formed only by those tumor cells that have survived all steps in a process that has been shown in many experimental studies to be a highly selective event. The results of studies on the distribution of radiolabelled mouse melanoma cells injected into syngeneic mice support the concept that the fate of tumor cells released into the bloodstream is determined by sequential and selective events, and introduces a third regulatory factor. Cells endowed with metastatic properties, isolated by cloning a heterogeneous tumor or selected from a metastasis, have a higher probability of forming metastases than cells not so endowed, yet this probability is not 100%. Metastasis should thus be considered as a selective, sequential and stochastic process. Interruption of the process at any stage will prevent the formation of metastatic disease. Hence, a better understanding of the metastatic process will provide the basis for rational approaches for the prevention or destruction of this most fatal aspect of cancer.

Animals↗

PubMed1990

Regional growth of different human melanomas as metastases in the brain of nude mice.

Cells from eight different human melanomas and two murine melanomas were injected into the internal carotid artery of anesthetized nude mice. Although all were injected by the same route, particular melanomas produced lesions in different regions of the brain. Two melanoma cell lines isolated originally from brain metastases in patients produced metastases predominantly in the brain parenchyma. In contrast, melanoma cells from subcutaneous or lymph node metastases produced more lesions in the meninges, choroid plexus, and ventricles than in the brain parenchyma. All of the melanomas grew in the brain after a direct intracerebral injection. The pattern of brain metastasis did not correlate with tumorigenicity per se or with the ability of the melanomas to grow in the lungs of nude mice. Two mouse melanomas showed different patterns of experimental metastasis after internal carotid artery injection, with one growing predominantly in the parenchyma and the other more frequently in the meninges and choroid plexus. The growth pattern of human melanoma metastasis in the brain of T cell-deficient nude mice suggests that it is determined by properties unique to each tumor interacting with the host's organ microenvironment.

Animals↗

PubMed1989

Unique patterns of brain metastasis produced by different human carcinomas in athymic nude mice.

The purpose of this study was to develop an in vivo model to study the growth pattern and biological behavior of brain metastases produced by different human carcinomas. To do so, human tumor cells from 8 different carcinomas of the colon, breast, kidney and lung were injected into athymic nude mice either by a direct intracerebral route or into the internal carotid artery. All carcinoma cells invaded through the blood-brain barrier and produced progressively growing lesions in the brain parenchyma. Unique patterns of growth were discernible among the carcinomas. Human colon carcinomas produced multiple lesions that spread by extension. Lung carcinoma cells produced widespread lesions throughout the brain. A very high degree of vascularization was associated with lesions produced by renal-cell carcinoma. The influence of estrogen on the growth of estrogen-receptor-positive human breast carcinoma cells was well demonstrated in this model. We conclude that the athymic nude mouse can be a useful model for studies of the biology and perhaps therapy of brain metastases produced by human carcinoma cells.

Animals↗

PubMed1989

Augmentation of antiproliferative activity of interferon alfa against human bladder tumor cell lines by encapsulation of interferon alfa within liposomes.

Present therapy for human bladder cancer includes the intravesical administration of antiproliferative agents, such as recombinant human interferon alfa (IFN-alpha). The administration of cytotoxic molecules encapsulated in liposomes could provide a more efficient method for such therapy. Therefore, we determined whether encapsulation of the recombinant human IFN-alpha hybrid BBDD within liposomes will produce antitumor effects against the human bladder cancer cell line 253J superior to those observed with free IFN-alpha. Adherent cells were cultured in medium alone, in medium containing different concentrations of IFN-alpha, or in medium containing multilamellar liposomes (phosphatidylcholine-phosphatidylserine at a molar ratio of 7:3) that encapsulated saline or IFN-alpha. Cell growth was determined 96-120 hours later. Additional control groups consisted of target cells cultured with free IFN-alpha or with IFN-alpha plus liposomes containing saline. Cytostasis mediated by free IFN-alpha alone or IFN-alpha in the presence of liposome-saline was identical and ranged from 0%-30% (10 IU/mL) to 45%-70% (1,000 IU/mL). Liposomes containing saline produced no effects. Liposome-encapsulated IFN-alpha produced significantly greater growth inhibition than free IFN-alpha: 40%-70% (10 IU/mL) and 80%-90% (1,000 IU/mL), respectively. Moreover, a 253J variant subline selected for resistance to free IFN-alpha was sensitive to IFN-alpha presented in liposomes. These data suggest that the encapsulation of antiproliferative agents such as IFN-alpha in liposomes can improve therapeutic results.

Carcinoma, Transitional Cell↗

PubMed1989

Correlation of growth capacity of human tumor cells in hard agarose with their in vivo proliferative capacity at specific metastatic sites.

The purpose of this study was to determine whether the degree of anchorage-independent growth of human tumor cells in increasing concentrations of agarose correlated with the capacity of the cells to produce experimental metastases in nude mice. Human melanoma, breast carcinoma, and colon carcinoma cells from parental lines and variants selected in vivo for metastasis and in vitro cloned lines were plated into medium containing 0.3%, 0.6%, 0.9%, or 1.2% of agarose. These cells were also injected into nude mice: intravenously for melanoma, into the mammary fat pad for breast carcinoma, and into the spleen for colon carcinoma. Production of tumor cell colonies in dense agarose (greater than 0.6%) correlated with production of experimental metastases in the lung (melanoma, breast carcinoma) or liver (colon carcinoma). We conclude that the degree of anchorage-independent growth of tumor cells can predict their biological behavior and metastatic potential in vivo. Thus, this technique may be useful for the isolation of metastatic cells from heterogeneous human neoplasms.

Animals↗