Biomedical subjects

M Gutman

Publications and source records attributed to M Gutman.

At least 73 records · Page 4Linked to original sources

PubMed1996

The effect of feeding dried tomato vines to beef cattle.

Dried Tomato vines (DTV) are used as a feedstuff in some beef cattle in Israel, despite the literature citation that tomato vines contain potentially harmful steroid alkaloids. A small-scale feeding trial over 42 d examined possible deleterious effects of feeding DTV, compared with wheat straw, in beef cows. No differences in hematological values, serum parameters for body weight were seen between the 2 groups. Steroid alkaloid content of the DTV was not examined, but toxic levels of nitrates were found. The main practical hazard in feeding DTV would appear to be from their potentially high nitrate content.

Alkaloids↗

PubMed1996

[Isolated limb perfusion with tumor necrosis factor for malignancies of the limbs].

Tumor necrosis factor (TNF) induces rapid necrosis in a variety of experimental neoplasms. However, its clinical application is limited by life-threatening systemic toxicity. Isolated limb perfusion (ILP) enables administration of large doses of TNF and cytotoxic drugs directly to the affected limb, avoiding systemic toxicity. We describe our experience in 20 consecutive patients (10 with melanoma and 10 with soft tissue sarcoma) treated with high-dose TNF and melphalan via ILP. ILP was performed via the external iliac (10 cases), femoral (2), popliteal (5) or brachial (3) vessels. Patients received 3-4 mg TNF to an upper, and 1-1.5 mg/kg to a lower extremity. Isolation efficiency was determined by injection of radiolabelled albumin. The procedure was successful in all 20 patients. Local complications included wound infection in 6 cases and hematoma in 2. 1 patient developed sepsis secondary to extensive necrosis of a large, secondarily infected tumor. The first 6 patients who underwent high-flow perfusion experienced systemic side-effects, mainly hypotension. These side-effects were eliminated when low-flow perfusion was introduced. The response rate was 100%. In the sarcoma group, 5/10 had complete response, and 5 partial response. Amputation or mutilating surgery was avoided in 9/10. Of the 10 with melanoma, 7 had complete, and 3 partial response. We conclude that administration of TNF via ILP is a safe and effective modality for treating advanced neoplasms of the limbs.

Adolescent↗

PubMed1995

Abnormalities in the CDKN2 (p16INK4/MTS-1) gene in human melanoma cells: relevance to tumor growth and metastasis.

The inhibitor of cyclin-dependent kinase 4, CDKN2 (also known as p16INK4 or MTS-1, multiple tumor suppressor gene 1), has been mapped to 9p21. The gene has been shown to be deleted or mutated in high frequency in human melanoma cell lines and familial melanoma patients, suggesting that it could be a melanoma suppressor gene. How these observations are related to tumorigenicity and metastasis of human melanoma is not clear however. To test the role of CDKN2 in human melanoma metastasis, 14 human melanoma cell lines with different metastatic abilities in nude mice were analysed for possible abnormalities in the CDKN2 gene. Homozygous deletions that resulted in a lack of gene expression were found in six of 14 cell lines tested. SSCP-direct sequencing revealed point mutations in three other cell lines. One cell line displayed CC to TT transitions which constitute a hallmark of ultraviolet-induced DNA damage. Overall, abnormalities in the CDKN2 gene were found in nine of 14 (64%) cell lines tested. Homozygous deletion and lack of gene expression were found in several low tumorigenic and nonmetastatic melanoma lines, whereas other metastatic cells did not exhibit abnormalities in the CDKN2 gene. These data suggest that the absence of normal CDKN2 does not confer growth advantage to melanoma cells in vivo and that the production of metastasis by human melanoma cells can occur in the absence of CDKN2 gene abnormalities.

Animals↗

PubMed1995

Ultraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin 8.

UV radiation has been shown to play a role in the initiation of human cutaneous melanoma, but its role in the development of malignant melanoma to the metastatic state is not very well defined. Although previous studies have concentrated on the effect of UV-B on the host immune response, the effect of UV-B on the tumor cells was not elucidated. Here we show that UV-B can induce interleukin 8 (IL-8) mRNA and protein secretion in human cutaneous melanoma with negligible expression of IL-8. UV-B-induced IL-8 was constitutively expressed 60 days after irradiation in tumors implanted in mice. Induction of IL-8 was UV-B dose dependent and blocked by cyclohexamide, indicating that de novo protein synthesis is required for its expression. The UV-irradiated cells demonstrated enhanced tumorigenicity and metastatic potential in nude mice. The increase in tumorigenicity and metastatic ability could be explained by the increase in Mr 72,000 type IV collagenase activity and angiogenesis attributed to the induction of IL-8 after irradiation. The acquisition of the metastatic phenotype induced by UV-B could not be attributed to abnormalities in the p53 or MTS-1 (p16INK4) genes. To the best of our knowledge, this is the first report to show that UV-B can increase the aggressiveness of human cutaneous melanoma for growth and metastasis.

Animals↗

PubMed1995

Direct correlation between expression of endogenous inducible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP 31362.

The purpose of this study was to determine whether the activation of inducible nitric oxide synthase (iNOS) can serve as a target for immunotherapeutic agents for treatment of murine reticulum cell sarcoma metastases. Liver metastases were established by the i.v. injection of M5076 cells into syngeneic C57BL/6 mice. Multiple systemic administrations of multilamellar vesicle-liposomes (MLV) containing the lipopeptide CGP 31362 (MLV-31362) or MLV-31362 combined with murine IFN-gamma eradicated the metastases. Tumor regression correlated with iNOS expression within the tumor lesions detected by Northern blot and immunohistochemistry techniques and with increased production of nitric oxide (NO). The administration of a specific iNOS inhibitor, NG-methyl-L-arginine, significantly decreased NO production and diminished the antitumor activities of the immunomodulators. Consistent with the regression of hepatic metastases, the combination of MLV-31362 and IFN-gamma synergistically induced iNOS gene expression, NO production, and apoptosis in the tumor cells under in vitro and in vivo conditions. The addition of NMA prevented the production of NO and apoptosis. These data imply that multiple systemic administrations of MLV-31362 plus IFN-gamma activate endogenous iNOS in sarcoma cells, which then undergo apoptosis, leading in turn to the regression of M5076 sarcoma hepatic metastases.

Adjuvants, Immunologic↗

PubMed1995

Regulation of interleukin-8 expression in human melanoma cells by the organ environment.

The in vitro expression level of interleukin-8 (IL-8) correlates with the metastatic potential of human melanoma cells. The purpose of this study was to determine whether the expression level of IL-8 in human melanoma cells is influenced by the organ microenvironment. A375P cells, a low metastatic human melanoma, and A375SM cells, a highly metastatic variant, were injected into the subcutis (s.c.), spleen (to produce liver metastases), and lateral tail vein (to produce lung metastases) of athymic nude mice. Northern blot and immunohistochemical analyses determined that s.c. tumors, lung lesions, and liver lesions expressed high, intermediate, and low IL-8, mRNA, and protein, respectively. This differential regulation of IL-8 was not due to the size or density of the lesions or to selection of subpopulations of cells. We based this conclusion on the results of three experiments: (a) melanoma cell lines established in culture from in vivo-growing tumors exhibited similar levels of IL-8 mRNA transcripts; (b) in a crossover experiment, the level of IL-8 mRNA was always high in A375 tumors reestablished in the skin and low in the tumors reestablished in the liver, regardless of whether the melanoma cells had been first harvested from s.c. or liver tumors; and (c) A375 melanoma cells cocultured with human keratinocytes produced high levels of IL-8 protein, whereas A375 cells cocultured with highly differentiated human hepatoma cells produced decreased levels. When A375P cells were then incubated with cytokines associated with keratinocytes (IL-1 and interferon beta) or hepatocytes (transforming growth factor alpha or beta), IL-1 enhanced the production of IL-8 protein, whereas TGF-beta decreased its production. These data show that IL-8 expression in melanoma cells is modulated by local host factors.

Adaptation, Psychological↗

PubMed1995

Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas.

We investigated the influence of interferons alpha, beta, and gamma (IFN-alpha, -beta, and -gamma) on the production of basic fibroblast growth factor (bFGF) by human renal carcinoma cells. The human renal carcinoma cell metastatic line SN12PM6 was established in culture from a lung metastasis and SN12PM6-resistant cells were selected in vitro for resistance to the antiproliferative effects of IFN-alpha or IFN-beta. IFN-alpha and IFN-beta, but not IFN-gamma, down-regulated the expression of bFGF at the mRNA and protein levels by a mechanism independent of their antiproliferative effects. Down-regulation of bFGF required a long exposure (> 4 days) of cells to low concentrations (> 10 units/ml) of IFN-alpha or IFN-beta. The withdrawal of IFN-alpha or IFN-beta from the medium permitted SN12PM6-resistant cells to resume production of bFGF. The incubation of human bladder, prostate, colon, and breast carcinoma cells with noncytostatic concentrations of IFN-alpha or IFN-beta also produced down-regulation of bFGF production.

Base Sequence↗

PubMed1995

Transfection with the inducible nitric oxide synthase gene suppresses tumorigenicity and abrogates metastasis by K-1735 murine melanoma cells.

Previous studies from our laboratory demonstrated an inverse relationship between the expression level of inducible nitric oxide synthase (iNOS) and the metastatic potential of murine K-1735 melanoma cells. The purpose of this study was to provide direct evidence that the expression of iNOS suppresses metastatic potential of melanoma cells. Highly metastatic K-1735 clone 4 cells (C4.P), which express low levels of iNOS, were transfected with a functional iNOS (C4.L8), inactive-mutated iNOS (C4.S2), or neomycin-resistance (C4.Neo) genes in medium containing 3 mM NG-methyl-L-arginine (NMA). Positive transfectants were identified by Southern and Northern blot analyses and homogeneous staining with a specific anti-iNOS monoclonal antibody. Semiconfluent cultures of C4.P (parental), C4.Neo.3 (control transfection), C4.S2.3 (inactive iNOS), and C4.L8.5 (functional iNOS) were harvested, and viable cells were injected intravenously into syngeneic C3H/HeN mice and allogeneic BALB/c nude mice. C4.P, C4.Neo.3, and C4.S2.3 cells were highly metastatic whereas C4.L8.5 cells were not metastatic. Experiments with [125I]dUrd-labeled tumor cells demonstrated that the initial arrest in the lung microvasculature did not differ among the lines, but that C4.L8.5 cells died by 48-72 h after injection. Enhanced survival of all K-1735 C4 cells (including C4.L8.5) was found in mice given twice daily injections of 20 mg NMA. The C4.L8.5 cells produced slow growing subcutaneous tumors in nude mice, whereas the other three lines produced fast growing tumors. In vitro studies confirmed that in the absence of NMA the expression of iNOS in C4.L8.5 cells induced apoptosis. Collectively, these data demonstrate that the expression of recombinant iNOS in melanoma cells is associated with apoptosis, suppression of tumorigenicity, and abrogation of metastasis.

Amino Acid Oxidoreductases↗

PubMed1995

Systemic leakage and side effects of tumor necrosis factor alpha administered via isolated limb perfusion can be manipulated by flow rate adjustment.

BACKGROUND: The tolerated systemic dose of recombinant tumor necrosis factor alpha (rTNF-alpha) is very limited, since its administration leads to a severe septic shock-like condition. Its implementation in isolated limb perfusion (ILP) for metastatic melanoma or advanced soft-tissue sarcoma confined to the limb facilitates doses of rTNF-alpha 10 times higher than the systemic tolerated dose. However, with the traditional high flow rate used in ILP, systemic leakage and side effects are not eliminated. OBJECTIVE: To determine if a lower perfusion flow rate would reduce leakage and consequently toxic effects. METHODS: Isolated limb perfusion was performed for melanoma and soft-tissue sarcoma confined to the limb using a flow rate of 869 +/- 122 mL/min in nine patients (group 1) and a lower rate of 286 +/- 62 mL/min in six patients (group 2). RESULTS: The systemic leakage rate was 12.5% +/- 2.9% in group 1, compared with 2.3% +/- 1.0% in group 2 (P = .003). Peak TNF-alpha levels were 29,000 +/- 2700 pg/mL in group 1, higher than 1580 +/- 1355 pg/mL in group 2 (P = .02). The tachycardia, hypotension, increased cardiac output, decreased systemic vascular resistance, bilirubinemia, elevation of liver enzyme levels, hypocholestrolemia, thrombocytopenia, and prolongation of prothrombin and partial thromboplastin times all observed in group 1 were significantly attenuated or eliminated in group 2. The limb PO2, PCO2, pH, and viability remained similar in both groups. Also, the tumor response rate remained high and was unaffected by the decrease in flow rate. CONCLUSIONS: Decreasing perfusion flow rate during ILP results in diminished leakage of TNF-alpha. Consequently, the systemic hemodynamic, metabolic, and hematologic toxic effects are virtually abolished.

Adolescent↗

PubMed1995

Suppression of tumor growth and metastasis of murine renal adenocarcinoma by syngeneic fibroblasts genetically engineered to secrete the JE/MCP-1 cytokine.

The murine monocyte chemoattractant protein 1, JE/MCP-1, like its human counterpart monocyte chemotactic and activating factor (MCAF), attracts monocytes-macrophages to tumor tissues. In previous studies we reported that expression of the JE/MCP-1 gene in murine colon carcinoma cells reduced their tumorigenicity and suppressed their metastatic potential. We now demonstrate that the growth and metastasis of the renal adenocarcinoma cell line RENCA are reduced when it was admixed with syngeneic fibroblasts engineered to secrete the JE/MCP-1 cytokine before injection. Culture supernatants of JE/MCP-1-expressing cells plus lipopolysaccharide (LPS) synergistically activated tumoricidal properties in syngeneic macrophages against RENCA cells. This activity was blocked by anti-JE/MCP-1 antibody, indicating that JE/MCP-1 was involved in priming the macrophages to respond to LPS. Moreover, alveolar macrophages isolated shortly after iv injections of JE/MCP-1 transfected cells were cytotoxic to RENCA cells in vitro. Collectively, these data suggest that in addition to its chemotactic properties, JE/MCP-1 can synergize with bacterial endotoxins to activate macrophages, thus providing a rationale for the use of the JE/MCP-1 protein as a modality for treatment of metastasis.

3T3 Cells↗

PubMed1995

Heterogeneity of cytokine and growth factor gene expression in human melanoma cells with different metastatic potentials.

The purpose of this study was to determine the mRNA expression level of multiple cytokine and growth factor genes in human malignant melanoma. Melanoma cells were isolated from several surgical specimens, adapted to growth in culture, characterized for their ability to produce experimental metastases in nude mice, and assessed for cytokine and growth factor steady-state gene expression. Highly metastatic in vivo- and in vitro-derived variants isolated from a single melanoma, A375, were also analyzed. Northern blot analyses revealed that all melanomas analyzed constitutively expressed steady-state mRNA transcripts for the growth and angiogenic factors, basic fibroblast growth factor (bFGF), and transforming growth factor alpha (TGF-alpha), which correlated with metastatic propensity. Only one highly metastatic melanoma, TXM-1, originally isolated from a lymph node metastasis, expressed mRNA transcripts specific for monocyte chemotactic and activating factor (MCAF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Similarly, of the nine melanomas examined, only TXM-1 expressed interleukin (IL)-1 alpha, IL-1 beta, and IL-6, important immunomodulatory cytokines. These data demonstrate the differential and heterogeneous expression of cytokine and growth factor genes in human malignant melanoma.

Animals↗

PubMed1995

Treatment of nude mice with 4-amidinoindan -1- one2 '- amidinohydrazone, a new S-adenosylmethionine decarboxylase inhibitor, delays growth and inhibits metastasis of human melanoma cells.

CGP 48664A (4-amidinoindan-1-one2'-amidinohydrazone) is a novel inhibitor of S-adenosyl-methionine decarboxylase (SAMDC), a key enzyme in the biosynthesis of polyamines, which are themselves essential for proliferation of mammalian cells. Seven different human melanoma cell lines were treated in vitro with CGP 48664A. High, intermediate and low levels of cytostasis were induced in four, one and two melanoma lines, respectively. This cytostasis was reversed by the addition of exogenous spermidine or spermine to the culture medium. The heterogeneous low metastatic (CGP 48664A-resistant) A375P cells and highly metastatic (CGP 48664A-sensitive) A375SM cells were implanted into the subcutis or injected intravenously into nude mice. Systemic daily administration of CGP 48664A significantly reduced the size of cutaneous lesions and the number of lung metastases in mice implanted with A375SM cells. No beneficial effects were found in mice injected with A375P cells. Drug activity was dose dependent, and maximal effects were observed when treatment began in mice with small tumour burdens. The data suggest that CGP 48664A is effective against melanoma metastasis in nude mice and that its activity should be tested in combination with other cytoreductive agents.

Adenosylmethionine Decarboxylase↗

PubMed1994

Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice.

We correlated the steady state transcription and protein secretion of interleukin 8 (IL-8) in 13 different human melanoma cell lines with their ability to grow and produce metastasis in nude mice. Highly metastatic cells expressed higher steady state levels of IL-8 mRNA transcripts than did low metastatic cells. In situ mRNA hybridization analyses confirmed the pattern of mRNA expression on a cellular level. Increased mRNA expression directly correlated with secretion of IL-8 protein as determined by enzyme-linked immunosorbent assay. Recombinant IL-8 stimulated the proliferation of low metastatic A375P cells in a dose-dependent manner, a stimulation that was abrogated by the use of a polyclonal antibody against IL-8. The data suggest that IL-8 can be an autocrine growth factor for human melanoma cells and that IL-8 is involved in melanoma metastasis.

Animals↗

PubMed1994

The dynamics of proton transfer at the C side of the mitochondrial membrane: picosecond and microsecond measurements.

The excited-state proton emitter, pyranine (8-hydroxypyrene-1,3,6-trisulfonate), was introduced into the inner aqueous space of inside-out submitochondrial particles (SMP). Upon initiation of respiration, the dye recorded acidification of this space. Incorporation of high concentrations of the dye (approximately 100 nmol/mg of protein) had no effect on the respiratory functions of the vesicles, nor on their capacity to execute delta microH(+)-coupled reverse electron transfer. The respiratory control ratio (RCR) remained as high as RCR > 4. Pulse irradiation of the dye caused photodissociation of the proton from the 8-hydroxy position. The release of the proton and its reaction with the matrix of the inner space of SMP were monitored at two time intervals: nanosecond fluorimetry measured the dissociation of the proton from the excited dye molecule (phi OH*), while microsecond spectroscopy followed the reaction between the proton and the ground-state anion (phi O-). Numerical integration of the differential rate equations describes the diffusion of protons in the perturbed system. The nanosecond measurements yield the physical characteristics of the aqueous phase that dissolves the dye. The apparent dielectric constant of that space is rather low (epsilon = 20). The diffusion coefficient of the proton is 2.3 x 10(-5) cm2/s, and the activity of water is aH2O = 0.87. All of these values imply that a large fraction of the intervesicular aqueous phase is taken up by the hydration layer of the lipids and proteins of the C side of the membrane. The microsecond dynamics measurements indicate that the rates of proton binding to the membrane surface components reach an equilibrium within 60 microseconds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Expression of the JE/MCP-1 gene suppresses metastatic potential in murine colon carcinoma cells.

The purpose of this study was to determine whether the expression of the JE/MCP-1 gene encoding for the monocyte chemottractant protein, MCP-1 (also known as monocyte chemotactic and activating factor MCAF, TDCF, and SMC-CF) can influence the metastatic properties of tumor cells. The highly metastatic murine colon carcinoma CT-26 cells, syngeneic to BALB/c mice that do not produce endogenous JE/MCP-1 protein, were transfected with a BCMGS-Neo expression vector (control) or a vector containing full-length JE cDNA. CT-26 parental cells, CT-26 Neo, and CT-26 JE/MCP-1-positive cells were injected into syngeneic or nude mice. The CT-26 JE/MCP-1-positive cells produced significantly fewer lung metastases. The decrease in incidence of metastasis was not due to the inability of the transfected cells to arrest in the lung vasculature or to differences in cell cycle time. CT-26 cells producing JE/MCP-1 were highly susceptible to lysis by syngeneic macrophages treated with subthreshold concentrations of lipopolysaccharide. In addition, culture supernatants of JE/MCP-1-expressing cells plus lipopolysaccharide synergistically activated tumoricidal properties in syngeneic macrophages. This activity was blocked by anti-JE/MCP-1 antibodies, indicating the involvement of the JE/MCP-1 molecule in this process. Moreover, purified JE/MCP-1 added to lipopolysaccharide-containing medium resulted in significant activation of macrophages against parental CT-26 cells. These data suggest that, in addition to its chemotactic properties, JE/MCP-1 can synergize with bacterial endotoxins to activate macrophages to become tumoricidal and, hence, could suppress metastasis.

Adenocarcinoma↗

PubMed1994

Leukocyte-induced angiogenesis and subcutaneous growth of B16 melanoma.

We investigated the mechanism(s) by which systemic administration of doxorubicin (DXR) produced growth retardation of B16 melanomas in the subcutis of syngeneic mice. DXR or saline was injected intravenously (i.v.) into C57BL/6 mice, and B16-BL6 cells were implanted subcutaneously (s.c.) on day 3, 7, or 21 after DXR treatment. In the DXR-pretreated mice, the tumors grew at a slower rate than in control (saline-treated) mice. The experiments were repeated with a B16 variant resistant to DXR with similar results. Tumor growth retardation correlated with extent of myelosuppression monitored by counting bone marrow cells, circulating leukocytes and peritoneal macrophages. In DXR-pretreated mice reconstituted with 1 x 10(7) viable syngeneic spleen cells, the s.c. tumors grew at a rate similar to that in control mice. DXR treatment and spleen cell reconstitution experiments were repeated in BALB/c athymic nude mice. The results were very similar. The growth of s.c. tumors was directly correlated with the degree of peritumoral vascularity. These data indicate that in addition to its well-documented direct antitumor effects, DXR may produce retardation of tumor growth by producing myelosuppression and, hence, inhibition of host cell-induced tumor angiogenesis.

Animals↗

PubMed1994

Parental effect on the humoral immune response to Escherichia coli and Newcastle disease virus in young broiler chicks.

Genetic and environmental variables influence animal resistance to disease infection. In addition, maternal effects were also found in studies with egg-type chicken lines. In our laboratory, meat-type chicken lines were divergently selected for either early or late maturation of the immune system, based on family and individual antibody responsiveness at 10 d of age. The high-antibody (HC) and low-antibody (LC) lines differed significantly in the early immune response to Escherichia coli, to Newcastle disease virus (NDV) vaccination, and to several other immune functions. Reciprocal crosses between the HC and LC lines were performed over 2 yr at three different locations. Immune responses to E. coli and NDV vaccination provided separate estimates of maternal and paternal effects. Dam effect on immune response to E. coli vaccine was significantly larger than sire effect; the antibody titer in both reciprocal crosses was intermediate between the parental lines, but the mean titer of the HC x LC cross was significantly lower than that of the LC x HC cross. Similar, but not significant, ranking of crosses was observed for the response to NDV. Evidently, the level of the offspring humoral immune response was more a dam than a sire effect.

Animals↗

PubMed1994

Organ site-dependent expression of basic fibroblast growth factor in human renal cell carcinoma cells.

We investigated the influence of organ microenvironment on the angiogenic phenotype in human renal cell carcinoma (HRCC) cells. HRCC line SN12C was established in vitro from a surgical specimen, and metastatic line SN12PM6 was isolated from a lung metastasis produced by parental cells implanted into the kidney of nude mice. SN12C (low metastasis) and SN12PM6 (high metastasis) cells were injected into the kidney or subcutis of nude mice. The kidney tumors were highly vascularized (as revealed by immunohistochemistry using antibodies against factor VIII), and metastatic, whereas the subcutaneous tumors were not. The expression of mRNA for basic fibroblast growth factor (bFGF) in kidney tumors was 10 to 20 times that found in subcutaneous tumors. Similar data were obtained at the protein level by using fluorescence activated cell sorting, immunohistochemistry, and enzyme-linked immunosorbent assay. bFGF was detected in the urine of mice with tumors in the kidney but not subcutaneous tumors. The level of bFGF in the serum of mice with kidney tumors was two to three times that in mice with subcutaneous tumors. The changes in bFGF expression in the tumors was transient. Collectively, these data indicate that the organ microenvironment can influence the expression level of bFGF in HRCC.

Animals↗