Immune response to polyoma tumor cells in mice—III. Stimulation of tumor cell growth in Vitro by spleen cells from immunized animals

Because thrombin-treated tumor cell-induced metastasis increases tumor nodule volume12 greater than nodule number, we studied the effect of thrombin on tumor cell growth in vitro and in vivo (murine B16F10 melanoma, human HCT8 colon carcinoma, DU145 prostate carcinoma). Tumor cell growth was measured after 3 to 7 days in 1% fetal calf serum (FCS) + RPMI 1640. We found that, whereas relatively low concentrations of thrombin, 0.1 to 0.5 U/mL (1-5 nmol/L) enhance tumor cell growth in vitro approximately 2- to 3-fold, higher concentrations, 0.5 to 1 U/mL (5-10 nmol/L) impaired cell growth approximately 2- to 4-fold. Impaired cell growth was associated with cell cycle arrest at G2M and increased pre-GoDNA, as well as apoptosis, measured by tumor cell binding to Annexin V and propidium iodide. Apoptosis was reversed with the general caspase inhibitor, FK-011. The enhancing and inhibiting effects were specific for thrombin (reversed with inactive diisopropyl-fluorophosphate [DFP]-thrombin) and mediated via the protease-activated receptor 1 (PAR-1). PAR-1 activation was demonstrated by (1) use of a cell line, B16F10, devoid of the 3 other thrombin receptors, PAR-3, PAR-4, and GPIb; and (2) greater sensitivity of PAR-1 transfected B16F10 and HCT8 cells to impaired cell growth/apoptosis, 3- and 14-fold, respectively. Thus, thrombin has a bimodal effect on PAR-1 in tumor cells: enhanced growth at low concentration, impaired growth/apoptosis at higher concentration.

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Donor lymphocyte infusions from Ad-sig-TAA/ecdCD40L vector prime-TAA/ecdCD40L protein boost (VPP) vaccinated allodonors decrease tumor cell growth post allograft

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3071 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3071-3071

Author(s):

A. B. Deisseroth ◽

Y. Tang ◽

H. Akbulut ◽

J. Maynard ◽

L. Petersen

Keyword(s):

Immune Response ◽

T Cells ◽

Cell Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Cd40 Ligand ◽

Cell Transplant ◽

Tumor Cell Growth ◽

Protein Boost ◽

Cd40l Expression

3071 Background: Individuals of advanced chronological age exhibit an impaired immune response to vaccines. This may be due to a reduction in the ratio of antigen naïve/memory CD4 and CD8 T cells and acquisition of functional defects in activated “helper” CD4 T cells (eg diminished CD40 ligand (CD40L) expression) during the aging process. Methods: In order to circumvent this defective response to vaccines in individuals in the fifth and sixth decades of life, our laboratory has developed an adenoviral vector (Ad-sig- TAA/ecdCD40L) vaccine which is designed for the in vivo target associated antigen (TAA) loading and activation of dendritic cells (DCs), and to overcome the absence of CD40L expression in activated CD4 helper T cells in older individuals. Results: The subcutaneous (sc) injection of this vector leads to the release of a fusion protein composed of a TAA linked to the extracellular domain (ecd) of the CD40 ligand (CD40L), which binds to the CD40 receptor on DCs, activates the DCs, and leads to the presentation of TAA fragments on Class I MHC. Two sc injections of the TAA/ecdCD40L protein as a booster following the sc administration of the Ad-sig-TAA/ecdCD40L vector (VPP) expands the magnitude of the cellular and humoral immune response induced by the vector in 18 month old aged mice as well as in younger mice. This vaccine decreased levels of negative regulatory CD4 FOXP3 T cells in tumor nodules. We administered TBI and an allogeneic stem cell transplant 7 days post sc injection of the E7 positive TC-1 cells. DLI from an Ad-sig-E7/ecdCD40L vector prime-E7/ecdCD40L protein boost vaccinated donor were injected iv 3 days post transplant, and a single E7/ecdCD40L protein boost sc vaccination one week thereafter. We found that the growth rate of the E7 positive TC-1 tumor cells post allograft was less in the vaccinated than in the control (injection of tumor cells followed in 7 days by TBI), or the animals in which the allograft recipient was vaccinated without DLI. Conclusions: Thus, the use of DLI from VPP vaccinated allodonors decreased tumor cell growth post allograft. No significant financial relationships to disclose.

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Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells

Blood ◽

10.1182/blood.v95.10.3133 ◽

2000 ◽

Vol 95 (10) ◽

pp. 3133-3138 ◽

Cited By ~ 90

Author(s):

Jasmine Zain ◽

Yao-Qi Huang ◽

XueSheng Feng ◽

Mary Lynn Nierodzik ◽

Jian-Jun Li ◽

...

Keyword(s):

Cell Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Calf Serum ◽

Annexin V ◽

Tumor Cell Growth ◽

Diisopropyl Fluorophosphate ◽

General Caspase Inhibitor

Abstract Because thrombin-treated tumor cell-induced metastasis increases tumor nodule volume12 greater than nodule number, we studied the effect of thrombin on tumor cell growth in vitro and in vivo (murine B16F10 melanoma, human HCT8 colon carcinoma, DU145 prostate carcinoma). Tumor cell growth was measured after 3 to 7 days in 1% fetal calf serum (FCS) + RPMI 1640. We found that, whereas relatively low concentrations of thrombin, 0.1 to 0.5 U/mL (1-5 nmol/L) enhance tumor cell growth in vitro approximately 2- to 3-fold, higher concentrations, 0.5 to 1 U/mL (5-10 nmol/L) impaired cell growth approximately 2- to 4-fold. Impaired cell growth was associated with cell cycle arrest at G2M and increased pre-GoDNA, as well as apoptosis, measured by tumor cell binding to Annexin V and propidium iodide. Apoptosis was reversed with the general caspase inhibitor, FK-011. The enhancing and inhibiting effects were specific for thrombin (reversed with inactive diisopropyl-fluorophosphate [DFP]-thrombin) and mediated via the protease-activated receptor 1 (PAR-1). PAR-1 activation was demonstrated by (1) use of a cell line, B16F10, devoid of the 3 other thrombin receptors, PAR-3, PAR-4, and GPIb; and (2) greater sensitivity of PAR-1 transfected B16F10 and HCT8 cells to impaired cell growth/apoptosis, 3- and 14-fold, respectively. Thus, thrombin has a bimodal effect on PAR-1 in tumor cells: enhanced growth at low concentration, impaired growth/apoptosis at higher concentration.

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The effect of the hypoferremic response on iron acquisition by and growth of murine lymphoma cells

Biochemistry and Cell Biology ◽

10.1139/o87-086 ◽

1987 ◽

Vol 65 (7) ◽

pp. 651-657 ◽

Cited By ~ 4

Author(s):

Margaret Caldwell ◽

Frederick Archibald

Keyword(s):

Cell Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Iron Acquisition ◽

Transferrin Saturation ◽

Tumor Burden ◽

Tumor Cell Growth ◽

Lymphoma Cells ◽

Fe Uptake

The hypoferremic response in C57 black mice during EL4 lymphoma cell growth was followed to determine if a lowered transferrin iron saturation inhibited iron acquisition and growth by these tumor cells. Although the lymphoma induced a strong hypoferremic response, it occurred late in the disease when the tumor burden was high and did not appear to effectively limit tumor cell growth, as all mice subsequently died. The induction of a hypoferremic response early in the disease with subcutaneous injections of turpentine also did not inhibit tumor cell growth. Parallel in vitro cell growth experiments revealed iron to be readily available to the lymphoma cells, regardless of whether the transferrin pool was 100, 50, or 10% saturated with iron. The dynamics of 59Fe uptake by the lymphoma cells from 50% saturated ferritransferrin were followed and saturation of iron uptake was found to occur at 150 nM iron and transferrin, far below physiological levels. Lowering transferrin saturation from 50 to 10% did not result in a proportional decrease in 59Fe uptake. Thus the ability of the EL4 tumor cells to obtain iron appeared to exceed the ability of a vigorous murine hypoferremic response to sequester it, suggesting that the hypoferremic response does not effectively limit EL4 ascites tumor cell growth.

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Immune regulation of the L5178Y murine tumor-dormant state. I. In vivo and in vitro effects of prostaglandin E2 and indomethacin on tumor cell growth.

Journal of Experimental Medicine ◽

10.1084/jem.164.4.1259 ◽

1986 ◽

Vol 164 (4) ◽

pp. 1259-1273 ◽

Cited By ~ 16

Author(s):

C M Liu ◽

T Okayasu ◽

P Goldman ◽

Y Suzuki ◽

K Suzuki ◽

...

Keyword(s):

Cell Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Peritoneal Cavity ◽

Host Cells ◽

Tumor Cell Growth ◽

Dormant State ◽

Peritoneal Cells

Immunization and intraperitoneal challenge of DBA/2 mice with L5178Y lymphoma cells results in the suppression and maintenance of the L5178Y cells in a tumor-dormant state in the peritoneal cavity for many months. Cell-mediated immune responses involving lymphocytes and macrophages are involved in maintenance of the tumor-dormant state. Macrophages that have increased immunosuppressive activity and that produce increased amounts of PGE2 appear in the peritoneal cavity of tumor-dormant mice before the breakdown of the tumor-dormant state and formation of ascitic tumors. We report here that the tumor-dormant state can be terminated with formation of ascitic tumors by treatment of tumor-dormant mice with PGE2. Treatment with indomethacin results in inhibition of tumor cell growth and elimination of all recoverable tumor cells. Cultures of peritoneal cells (PC) from mice harboring L5178Y cells in a tumor-dormant state were used to analyze the PGE2 and indomethacin effects. Tumor cells did not grow out in the high-cell density PC cultures prepared from many tumor-dormant mice, but addition of PGE2 to these cultures resulted in tumor cell growth. The tumor cell growth that did occur in the PC cultures from some tumor-dormant mice was associated with PGE2 production by the associated host cells, and the addition of indomethacin to these cultures inhibited both PGE2 synthesis and tumor cell growth. Removal of plastic-adherent cells from the PC cultures eliminated the restraint on tumor cell growth. These experiments suggest that L5178Y tumor cells are maintained in a tumor-dormant state by host peritoneal cells, which are under PGE2 regulation.

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