Neoplastic cell spreading in rodent transplantable tumor models. II. Santamaria tumor (syngeneic keratinizing squamous cell carcinoma)

A syngeneic transplantable tumor was obtained in our laboratory by inducing a skin squamous cell carcinoma in BALB/c mice treated with benzo(a) pyrene and UVA. Single tumor cell suspensions obtained by finely disrupted tumor masses were either i.p. or intramuscularly injected and developed (100% takes) invasive tumors maintaining in subsequent analogue serial transplantations identical histopathological aspects. May Grünwald Giemsa stained organ imprints of tumor bearing mice showed disseminated tumor cells as well as a number of infiltrating host defense cells (principally neutrophils) despite the mice were in a terminal status. May Grünwald Giemsa stained cryostat sections showed numerous mast cells lining the invasive tumor front and allowed to detect in the liver tumor cells migrated from primary tumor (localized in femoral muscle) adhering to endothelial cells may be to perform extravasation.     

Ascitic and solid Ehrlich tumor inhibition by Chenopodium ambrosioides L. treatment

The leaves of Chenopodium ambrosioides L. [Chenopodiaceae] ('mastruz') have been indicated for the treatment of several diseases, among which the cancer. There are no results focusing the effect of C. ambrosioides treatment on tumor development in vivo. The aim of this study was to investigate the effect of treatment with C. ambrosioides on Ehrlich tumor development. Swiss mice were treated by intraperitoneal route (i.p.) with hydroalcoholic extract from leaves of C. ambrosioides (5 mg/kg) or with PBS (control group) 48 h before or 48 h later the Ehrlich tumor implantation. The tumor cells were implanted on the left footpad (solid tumor) or in the peritoneal cavity (ascitic tumor). To determine the solid tumor growth, footpad was measured each 2 days until the fourteenth day, when the feet were weighed. Ascitic tumor development was evaluated after 8 days of tumor implantation by quantification of the ascitic fluid volume and tumor cell number. The i.p. administration of C. ambrosioides extract before or after the tumor implantation significantly inhibited the solid and ascitic Ehrlich tumor forms. This inhibition was observed in ascitic tumor cell number, in the ascitic volume, in the tumor-bearing foot size and foot weight when compared to control mice. The treatments also increased the survival of tumor-bearing mice. In conclusion, C. ambrosioides has a potent anti-tumoral effect which was evident with a small dose and even when the treatment was given two days after the tumor implantation. This effect is probably related with anti-oxidant properties of C. ambrosioides.     

The allogeneic effect on tumor growth. II. Suppression of both ascitic and solid MOPC 315 plasmacytoma by the graft-vs-host reaction, with pathologic correlation.

The growth of an ascitic murine plasmacytoma, MOPC 315, can be retarded in CAF1 hybrid host mice by the i.p. injection of donor lymphoid cells. The graft-vs-host reaction can be established by a variety of donor cells, including parental BALB/c and A/J and congenic inbred B10.D2 which share the major histocompatibility locus with BALB/c(H-2d). Optimal results are consistently obtained when parental BALB/c spleen cells are injected before tumor inoculation, and a second dose of donor spleen cells injected 1 week later. This aloogeneic effect on tumor growth is manifested by delayed appearance of the tumor and prolonged host survival. Pathologic studies on the ascites tumor indicated that the allogeneic effect suppresses the initial appearance and early growth of the plasmacytoma. However, once established, MOPC 315 grows rapidly and fatally in both control mice and recipients of donor lymphoid cells. Further, a subcutaneous implant of MOPC 315 is suppressed by an allogeneic effect established either i.v. with BALB/c spleen cells before tumor inoculation or by BALB/c spleen cells administered subcutaneously at the time of MOPC 315 implant. Thirty percent of mice treated by i.v. or subcutaneous donor lymphoid cells were tumor free at 150 days after tumor inoculation.     

Effect of Pfaffia paniculata (Brazilian ginseng) on the Ehrlich tumor in its ascitic form

The roots of Pfaffia paniculata (Brazilian ginseng) have been indicated for the treatment of several diseases, among which the cancer. The purpose of this study was to investigate experimentally the possible antineoplastic effect of this root. Firstly, a toxicity study was performed in which the doses of 400 and 200 mg/Kg of the powdered root were administered by gavage for 10 days to BALB/cICB mice. The mice did not lose weight during the treatment. No increase in serum alanine-aminotransferase neither histopathological alteration (liver, kidney and spleen) was observed in mice treated with P. paniculata. The effect of this root on the ascitic Ehrlich tumor in BALB/cICB mice was then investigated. Male mice received, by gavage, once a day, 200 mg/Kg of the powdered root of P. paniculata or distilled water, as control, for 20 days. This protocol started 10 days before tumor inoculation with 5 x 10(6) cells i.p., and lasted until 10 days after. The ascitic tumor was evaluated by the quantification of the volume of the ascitic fluid, relative number of tumor cells and total number of tumor cells. A decrease in the total ascitic volume was observed in P. paniculata treated mice, that was followed by a numerical decrease in the total number of Ehrlich tumor cells. These results may indicate that P. paniculata anti-inflammatory effects were responsible by the decrease in the total ascitic fluid. In addition, the presence of tumor-cell inhibitory factors in P. paniculata roots is in agreement with other in vitro studies. The mechanisms of such tumor inhibition should be further investigated.     

Morphological characterization of lymphoid cells conjugates with scattered tumor target cells in organ imprints of Yoshida ascites bearing rats

The authors analysed morphologically the ability of host effector cells to bind disseminated tumor target cells (pre-lysis) in vivo. Scattered tumor cells are morphologically visible stained with May Grünwald-Giemsa in the lung, liver, kidney, and spleen imprints of Yoshida ascites tumor bearing rats. Lymphoid cells can be seen binding disseminated tumor target cells in organs but not in the peritoneal cavity. This model may provide a useful technique for morphological studies on the in vivo conjugation capacity of host effector cells against tumor target cells.     

The bradykinin B1 receptor antagonist R-954 inhibits Ehrlich tumor growth in rodents

The present study investigated the effects of a new bradykinin B₁ receptor antagonist, R-954, on the development of Ehrlich ascitic tumor (EAT) induced by the intraperitoneal inoculation of EAT cells in mice and the formation of a solid tumor by the subcutaneous injection of the cells in rat paw. The development of the tumor was associated with an increase in mouse total cell counts in bone marrow (10.8-fold), ascitic fluid (14.6-fold), and blood (12.6-fold). R-954 (2 mg/kg, s.c.) significantly reduced the ascitic fluid volume (63.7%) and the mouse weight gain (30.5%) after 10 consecutive days of treatment. The B₁ antagonist as well as the anti-neoplasic drug vincristine also significantly inhibited the increase in total cell count in bone marrow, ascitic fluid, and blood. R-954 reduced significantly the total protein extravasation (57.3%), the production of nitric oxide (56%), PGE₂ production (82%), and TNFα release (85.7%) in mice peritoneal cavity whereas vincristine reduced the release of these inflammatory mediators by 84-94%. The increase in paw edema after intraplantar injection of EAT cells was reduced by approximately 52% by either R-954 or vincristine treatment. In conclusion, this study presents for the first time the antitumoral activity of a new bradykinin B₁ receptor antagonist on ascitic and solid tumors induced by Ehrlich cell inoculation in mice and rats.     

Tryptophan degradation in transplanted tumor cells undergoing rejection

The depletion of an essential amino acid, tryptophan, caused by indoleamine 2,3-dioxygenase induction in vitro, has been shown to be due to a mechanism that is used in self-defense against inhaled microorganisms and tumor growth. In this communication, we report the results of measuring dioxygenase activity in the peritoneal exudate cells and tumor cytotoxicity at the transplantation loci after in vivo transplantation of tumor cells into the peritoneal cavity of syngeneic or allogeneic strains of mice. The enzyme was induced only when the tumor cells were being rejected from allogeneic animals and no change was observed when the cells continued to grow in syngeneic animals. Furthermore, when the syngeneic tumor cells in a diffusion chamber were i.p. transplanted simultaneously with i.p. injection of allogeneic tumor cells, the enzyme was induced not only in allografted tumor cells but also in the syngeneic tumor cells. Under these conditions, the tumor cells in the diffusion chamber ceased to grow and 50% of the cells were rejected. To determine the type of cells containing the induced enzyme, the peritoneal exudate cells (tumor cells and host cells--mostly small lymphocytes) were separated into six fractions by sedimentation under gravity and by differential centrifugation. Approximately 80% of total enzyme activity was localized in a tumor-rich fraction (98.9% purity), whereas only 0.2% of the activity was found in a lymphocyte-rich fraction (99.5% purity). The localization of indoleamine 2,3-dioxygenase in the tumor cells was confirmed by complement-dependent lysis with specific antibodies against tumor and host cells.     

Diazepam effects on Ehrlich tumor growth and macrophage activity in mice

Besides the central gabaergic receptors described for benzodiazepines, peripheral type binding sites (PBR) were also identified for these molecules in endocrine steroidogenic tissues, immune organs and cells, such as macrophages and lymphocytes. PBR activation was reported to decrease innate immunity and host defense. The present experiment was designed to analyze the effects of diazepam on Ehrlich tumor growth, and on macrophage activity of Ehrlich tumor bearing mice. Results showed that diazepam (3.0 mg/kg/day, for 7 days) increased the number of Ehrlich tumor cells and the volume of tumor-induced ascitic fluid. These effects were not observed after smaller doses of diazepam, suggesting a dose-dependant effect. Furthermore, our results show that 3.0 mg/kg of diazepam, administered daily, for 2 days, decreased (1) the number of peritoneal leukocytes retrieved after injection of the Ehrlich tumor, (2) the percents of macrophage spreading, and (3) the levels of macrophage NO production. Diazepam (3.0 mg/kg/day for 2 days) had no effect on macrophage phagocytosis or on H2O2 production. The present data is discussed based on a direct and/or indirect action of diazepam. Particularly, our findings might be due to a direct effect of diazepam on PBRs present on macrophages and tumor cells, or could still be mediated by PBR stimulation within the hypothalamus-pituitary-adrenal (HPA) axis.     

Effects of thymoquinone on liver miRNAs and oxidative stress in Ehrlich acid mouse solid tumor model

We investigated the effects of thymoquinone (TQ) on the expression of liver microRNAs (miRNAs), liver histopathology and oxidative stress in Ehrlich acid solid tumor model induced mice. We used 24 male BALB/c mice divided randomly into three groups. Control (C) group mice were injected intraperitoneally (i.p.) with 0.5 ml saline for four weeks. Tumor (T) group mice were injected i.p. with 0.5 ml saline for four weeks, then Ehrlich acid tumor cells were injected subcutaneously into the neck to induce solid tumor formation. TQ (T + Tq) group mice injected i.p. with 10 mg/kg TQ for four weeks, then Ehrlich acid tumor cells were injected subcutaneously into the neck of the mice in this group to induce solid tumor formation. At the end of the study, liver from all groups were removed for histopathological and miRNAs analysis, and oxidative stress measurement. We found that the expression of miR-206b-3p was up-regulated and the oxidative stress and necrosis increased in the liver tissue of mice with Ehrlich acid solid tumor. TQ application decreased the oxidative stress, prevented necrosis, increased regeneration and down-regulated the expression of miR-206b-3p in the liver tissue.     

In vivo and in vitro induction of natural killer cells by cloned human tumor necrosis factor

Summary The natural killer (NK) cell activity of mice in the peritoneal cavity is very low or undetectable and testing peritoneal NK cells is a useful model for studying the influence of activating substances upon local injection. Injection of tumor necrosis factor (TNF) at doses of 10–200 ng caused a marked activation of NK cell activity which was maximal after 24 h and declined rapidly on day 2. A similar effect was observed when interferons alpha and beta were injected, and there were additive results when interferon was injected together with TNF. The NK cell nature of the effector cells activated by TNF was substantiated by the finding that previous injection with anti-asialo GM 1 antibody prevented activation. Interferon could not be detected in the peritoneal wash fluid after injection of TNF suggesting interferon-independent activation. In further experiments after i.p. injection of TNF peritoneal exudate cells (PECs) only killed YAC-1 targets in a 4-h assay. There was no additional killing in an 18-h assay towards neither YAC-1 cells or P815 cells, suggesting that macrophages were not involved. Furthermore TNF was also active in vitro by activating NK cells in isolated human peripheral blood cells. However in the PECs stimulated in vitro no significant induction of cytotoxic capacities by TNF was measured. Our data suggest that the action of TNF is not restricted to the lysis of tumor cells but can also induce immunological properties in the host defense against virus infections and neoplasms.     

Investigation on the effect of peptides mixture from tumor cells inducing anti-tumor specific immune response

The peptides mixture was prepared from tumor cells by freezing-thawing cells, precipitation by heating, followed by acidification of the solution. The activation and proliferation of mouse splenocytes by HSP70-peptide complex, formed by the binding of HSP70 and peptides in vitro, were observed, so was the specific cytotoxicity of the proliferative lymphocytes to tumor cells. The phenotypes of the proliferative lymphocytes were analyzed by a flow cytometer. BALB/c mice inoculated with H22 hepatocarcinoma cells in peritoneal cavity or hind thigh were immunized by injection with HSP70-peptides complex to observe the inhibitory effect of the immunization on tumor and lifetime of tumor-bearing mice. On the other hand, blood samples were collected from the immunized mice to check the functions of liver and kidney. The results showed that the peptides mixture from tumor cells contained tumor-specific antigen peptides which could be presented by HSP70 to activate lymphocytes in vitro, the proliferative lymphocyt     

IL-10-deficient mice demonstrate multiple organ failure and increased mortality during Escherichia coli peritonitis despite an accelerated bacterial clearance

To determine the role of endogenous IL-10 in local antibacterial host defense and in the development of a systemic inflammatory response syndrome during abdominal sepsis, IL-10 gene-deficient (IL-10(-/-)) and wild-type (IL-10(+/+)) mice received an i.p. injection with Escherichia coli. Peritonitis was associated with a bacterial dose-dependent increase in IL-10 concentrations in peritoneal fluid and plasma. The recovery of E. coli from the peritoneal fluid, blood, and lungs was diminished in IL-10(-/-) mice, indicating that endogenous IL-10 impaired bacterial clearance. Despite a lower bacterial load, IL-10(-/-) mice had higher concentrations of TNF, macrophage inflammatory protein-2 and keratinocyte in peritoneal fluid and plasma, and demonstrated more severe multiple organ damage as indicated by clinical chemistry and histopathology. Furthermore, IL-10(-/-) mice showed an increased neutrophil recruitment to the peritoneal cavity. To examine the role of elevated TNF levels in the altered host response in IL-10(-/-) mice, the effect of a neutralizing anti-TNF mAb was determined. Anti-TNF did not influence the clearance of E. coli in either IL-10(+/+) or IL-10(-/-) mice. Furthermore, anti-TNF did not affect leukocyte influx in the peritoneal fluid, multiple organ damage, or survival in IL-10(+/+) mice. In IL-10(-/-) mice, anti-TNF partially attenuated neutrophil recruitment and multiple organ damage, and prevented the increased lethality. These data suggest that although endogenous IL-10 facilitates the outgrowth and dissemination of bacteria during E. coli peritonitis, it protects mice from lethality by attenuating the development of a systemic inflammatory response syndrome by a mechanism that involves inhibition of TNF release.     

Human immunodeficiency virus (HIV)-infected tumor xenografts as an in vivo model for antiviral therapy: role of alpha/beta interferon in restriction of tumor growth in nude mice injected with HIV-infected U937 tumor cells.

The host factors involved in the restriction of tumor growth were studied in nude mice transplanted with a cloned line of chronically human immunodeficiency virus (HIV)-infected U937 cells. HIV-infected and uninfected U937 cells exhibited the same growth patterns in culture. However, HIV-infected cells were not tumorigenic when injected subcutaneously in nude mice, whereas large solid tumors were observed in mice injected with uninfected U937 cells. Injection of nude mice with antibody to alpha/beta interferon (IFN-alpha/beta) enabled HIV-infected U937 cells to grow progressively in approximately 90 to 100% of mice. HIV-infected U937 cells formed solid tumors in the majority (60 to 90%) of either immunosuppressed (splenectomized, irradiated, and anti-asialo-GM1-treated) or genetically immunodeficient (bg/nu/xid) nude mice. In mice treated with antibodies to IFN-alpha/beta with established HIV-positive tumors, a direct correlation was found between p24 antigenemia and tumor size. Treatment of established HIV-positive U937 cell tumors with human IFN-alpha or mouse IFN-alpha/beta resulted in a clear-cut inhibition of both tumor growth and p24 HIV antigenemia. In contrast, treatment with tumor necrosis factor alpha markedly inhibited tumor growth but did not significantly decrease serum p24 levels. 3'-Azido-3'-deoxythymidine treatment did not affect either tumor growth or the levels of serum p24 antigen. These data indicate that endogenous IFN-alpha/beta is a crucial factor in the restriction of both tumor growth and p24 antigenemia in mice injected with HIV-infected tumor cells. Moreover, the results suggest that the development of HIV-1 p24 antigenemia in athymic immunosuppressed mice may represent an interesting in vivo model for anti-HIV therapy.     

Effects of radiation on host-tumor interactions using the multicellular tumor spheroid model

Summary Use of the multicellular tumor spheroid as a tumor model allows separate host or tumor treatment with ionizing radiation and examination of the effects on host-tumor immune interactions. Spheroids of EMT6/Ro, a BALB/c mammary tumor were implanted into the peritoneal cavity of syngeneic immunized mice, recovered, and dissociated into single cells. Cytolytic activity of mature spheroid associated cells and peritoneal cells was resistant to radiation doses as high as 1000 rads when irradiated directly prior to assay. Mice irradiated (200, 400, 700 rads) 24 h prior to spheroid injection had an increased number of tumor cells and decreased number of tumor infiltrating and peritoneal host cells upon spheroid recovery. This was paralleled by an increased colony forming efficiency per spheroid. Cytolytic activity of the spheroid associated cells against radiolabeled EMT6 cells was in many cases decreased with radiation although lysis was the same on a per cell basis. Cytolytic activity by peritoneal cells from these mice increased with dose as measured on a per cell basis. This activity from irradiated animals was carried out by a Thyl⁺ cell.     

Investigation on the effect of peptides mixture from tumor cells inducing anti-tumor specific immune response

The peptides mixture was prepared from tumor cells by freezingthawing cells, precipitation by heating, followed by acidification of the solution. The activation and proliferation of mouse splenocytes by HSP70-peptide complex, formed by the binding of HSP70 and peptides in vitro, were observed, so was the specific cytotoxicity of the proliferative lymphocytes to tumor cells. The phenotypes of the proliferative lymphocytes were analyzed by a flow cytometer. BALB/c mice inoculated with H22 hepatocarcinoma cells in peritoneal cavity or hind thigh were immunized by injection with HSP70-peptides complex to observe the inhibitory effect of the immunization on tumor and lifetime of tumor-bearing mice. On the other hand, blood samples were collected from the immunized mice to check the functions of liver and kidney. The results showed that the peptides mixture from tumor cells contained tumor-specific antigen peptides which could be presented by HSP70 to activate lymphocytes in vitro, the proliferative lymphocytes were T cells which were specifically cytotoxic to tumor cells, the in vivo growth of both ascitic and solid carcinoma could be suppressed by immunization with HSP70-peptides and the lifetime of tumor-bearing mice was prolonged, the in vivo immunization with HSP70-H22-peptides had no impact on the function of mouse liver and kidney, suggesting that there was no occurrence of autoimmunity in vivo after immunization.     

Intraperitoneal amyloid formation by amyloid enhancing factor--rich macrophages in ascitic fluid.

Although resident peritoneal cells from amyloidotic mice (amyloidotic peritoneal cells) are capable of processing the precursor protein of secondary amyloidosis, serum amyloid A (SAA) to amyloid fibrils, the peritoneum is a rare site for amyloid deposition. This is considered to be due to a deficiency of SAA in the peritoneum. To increase the supply of SAA to the peritoneum, ascitic fluid containing about the same protein constituents as in the serum was induced in mice. Amyloidotic peritoneal cells were packed in a microchamber which was shielded with filter membranes, and cultured in ascitic fluid supplemented with additional inflammatory factors. On the 7th day, Congo red-positive structures which showed green birefringence under polarized light were found inside and occasionally outside the chamber. By anti-AA or -SAA immunostaining, amyloid deposits and the cell surfaces of macrophages were positive. Immunologic depletion of T- and B-lymphocytes from the amyloidotic peritoneal cells did not adversely effect the amyloid formation in microchambers. These results suggest that either ascitic fluid containing sufficient amounts of SAA, or peritoneal macrophages with a high amyloid enhancing factor (AEF) activity are indispensable for AA amyloid fibrillogenesis in the peritoneum.     

Nitrogen metabolism in tumor bearing mice

In experiments with whole animals infested with a highly malignant strain of Ehrlich ascites tumor cells, serial concentrations of amino acids were determined for host plasma, ascitic fluid, and tumor cells, throughout tumor development. Concentration gradients of glutamine, asparagine, valine, leucine, isoleucine, phenylalanine, tyrosine, histidine, tryptophan, arginine, serine, methionine, and taurine from the host plasma toward the ascitic liquid were established; while on the other hand, concentration gradients from the ascitic liquid toward the plasma were established for glutamate, aspartate, glycine, alanine, proline, and threonine. With the exception of aspartate the concentrations of these amino acids were highest inside the cells. Arginine was the only amino acid not detected in tumor cells. In vitro incubations of tumor cells in the presence of glutamine and/or glucose, as the energy and nitrogen sources, confirmed the amino acid fluxes previously deduced from the observed relative concentrations of amino acids in plasma, ascitic liquid, and tumor cells, suggesting that glutamate, alanine, aspartate, glycine, and serine can be produced by tumors. These findings support that changes in amino acid patterns occurring in the host system are related to tumor development.     

Proliferative response of lymphocytes from ovarian cancer patients to autologous tumor cells

Summary Peripheral blood lymphocytes (PBL) from 43 patients with histologically confirmed ovarian carcinoma were stimulated in mixed lymphocyte-tumor culture (MLTC) with purified autologous tumor cells. Positive results, assessed as lymphocyte proliferation, were observed in 21 cases (48.8%). Lymphoid cells associated with ascitic fluid or infiltrating solid masses were in general less reactive than PBL as only 3/11 cases had positive MLTC. Tumor cells isolated from peritoneal effusions showed no significant difference in stimulatory potential as compared to the primary tumor. These results suggest that in an appreciable proportion of ovarian carcinoma patients (approximately 50%), lymphocytes have the potential to react to autologous tumor cells. Comprehension of the immunological mechanisms of antitumor resistance may have direct practical relevance for more effective treatment of neoplasms.     

Tumoricidal effect of human macrophage-colony-stimulating factor against human-ovarian-carcinoma-bearing athymic mice and its therapeutic effect when combined with cisplatin

The effect of human macrophage-colony-stimulating factor (hM-CSF) on tumoricidal activity was examined in athymic mice bearing the human ovarian cancer cell line, HRA, injected intraperitoneally (i.p.). The survival period and survival rate in the groups treated daily with hM-CSF were significantly longer (P<0.01) than in the untreated group. The peritoneal cell smears showed that ascitic tumor cells were markedly decreased in the hM-CSF-treated groups, and macrophages phagocytosed tumor cells, indicating a contact-mediated direct cytolysis. The combined therapeutic effects of cisplatin and hM-CSF on HRA-bearing athymic mice were also studied. The mean survival period was 25.4, 47.2, 42.4 and 67.4 days, respectively, in the untreated group, and in the groups treated with cisplatin alone, with hM-CSF alone, and with combined cisplatin and hM-CSF. The survival period and rate were significantly longer (P<0.01) in the group treated with combined cisplatin and hM-CSF than in those treated with cisplatin or hM-CSF alone, indicating the therapeutic effectiveness of the combined use. Morever, hM-CSF is effective against granulocytopenia due to bone marrow suppression caused by cisplatin. Our data demonstrate that hM-CSF administered i.p. has a tumoricidal activity in athymic mice bearing human ovarian cancer i.p., which is mediated by activated macrophages, and that the combined administration of cisplatin and hM-CSF has a significant therapeutic effect.     

Significance of host heparanase in promoting tumor growth and metastasis

Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth and metastasis. We have utilized mice over-expressing (Hpa-tg) heparanase to reveal the role of host heparanase in tumor initiation, growth and metastasis. While in wild type mice tumor development in response to DMBA carcinogenesis was restricted to the mammary gland, Hpa-tg mice developed tumors also in their lungs and liver, associating with reduced survival of the tumor-bearing mice. Consistently, xenograft tumors (lymphoma, melanoma, lung carcinoma, pancreatic carcinoma) transplanted in Hpa-tg mice exhibited accelerated tumor growth and shorter survival of the tumor-bearing mice compared with wild type mice. Hpa-tg mice were also more prone to the development of metastases following intravenous or subcutaneous injection of tumor cells. In some models, the growth advantage was associated with infiltration of heparanase-high host cells into the tumors. However, in other models, heparanase-high host cells were not detected in the primary tumor, implying that the growth advantage in Hpa-tg mice is due to systemic factors. Indeed, we found that plasma from Hpa-tg mice enhanced tumor cell migration and invasion attributed to increased levels of pro-tumorigenic factors (i.e., RANKL, SPARC, MIP-2) in the plasma of Hpa-Tg vs. wild type mice. Furthermore, tumor aggressiveness and short survival time were demonstrated in wild type mice transplanted with bone marrow derived from Hpa-tg but not wild type mice. These results were attributed, among other factors, to upregulation of pro-tumorigenic (i.e., IL35⁺) and downregulation of anti-tumorigenic (i.e., IFN-γ⁺) T-cell subpopulations in the spleen, lymph nodes and blood of Hpa-tg vs. wild type mice and their increased infiltration into the primary tumor. Collectively, our results emphasize the significance of host heparanase in mediating the pro-tumorigenic and pro-metastatic interactions between the tumor cells and the host tumor microenvironment, immune cells and systemic factors.