[Thermoradiotherapy in animal experimentation: tumor growth and tumor cure (author's transl)].
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[Significance of immunosuppression for tumor growth and tumor propagation in an allogeneic study].
Summarizing we can establish that by an adequate intensive immunosuppression the successful performance of a tumour transplantation, even of a heterologous one, is possible. However, the tolerance of the heterologous tumour remains only for as long as there exists an immunosuppression. The following rejection is unequivical at the typical morphological picture. These finding should remind of the possible effects of the immunosuppression in the syngenic system, particularly in the tumour patients, and also of the fact that all immunosupressively acting measures in this group of patients must undergo a strong criticizm.
Animals↗
Enhancing effect of thyroxine on tumor growth and metastases in syngeneic mouse tumor systems.
We studied the effect of thyroxine treatment on tumor growth and metastases resulting from tumor implants on the hind feet of mice in two syngeneic systems. In control, untreated A/Jax mice, tumor Sarcoma 1 at Day 14 after implantation had average tumor weight of 582 +/- 60 (S.D.) mg and showed an incidence of 57% metastases to regional popliteal nodes and 5% metastases to thymus. In contrast, the thyroxine-treated group (40 microgram/mouse s.c., 5 times/week for 1 month) had an average tumor weight of 808 +/- 56 mg (p less than 0.001), and metastases to popliteal nodes and thymus were 90 and 35%, respectively. In another syngeneic tumor system, Lewis fibrosarcoma was implanted in C57BL/6J mice, and the tumor weight and metastatic index (derived from the number and size of the pulmonary tumor foci) were determined at Day 28. Again, the synthetic L-thyroxine treated group showed a significant enhancement tumor growth and metastatic index. The mean tumor weight in the treated group was 385 +/- 26 mg (control, 694 +/- 25 mg; p less than 0.005) and metastatic index was 84 +/- 29 (control, 30 +/- 25; p less than 0.001). Induced hypothyroidism (treatment with 131I, 100 microCi/mouse i.p.) showed the reverse effect on both tumor systems. These results suggest that both tumor systems are dependent on thyroid hormones for their growth and spread.
Animals↗
Kinetic models of C3H mouse mammary tumor growth: implications regarding tumor cell loss.
Three models of tumor cell loss are described. The effects of cell loss on other cellular kinetic parameters are evaluated, and experiments which may distinguish among the models are discussed. Each model is based on a different cell-loss mechanism, and equations for the cell-cycle, cell-frequency distribution, the growth of both the proliferating and non-proliferating cell population, the growth fraction (GF), and the relative rate of volumetric growth, (dV/dt)/V, are derived. The following types of data are simulated for each model: the pulse labelling index, the mitotic index, and the labeling index as a function of time after a single or a series of 3H-TdR injections. The relative volumetric growth rate has the same mathematical form for each model. The PLM curves predicted by each model for the tumor lines studied (S102F and Slow) are not appreciably different. The predicted initial labeling index and mitotic index may differ significantly among the models depending upon the tumor line. The most striking difference among the models lies in the predictions regarding the labeling index as a function of time after a single or after a series of 3H-TdR injections. These types of labeling experiments should be valuable for distinguishing the different cell-loss mechanisms in solid tumors.
Animals↗
Opposite effects of T-cells on syngeneic tumor growth in vivo: tumor inhibition by mature lymphocytes and enhancement of the same tumors by immature cells.
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Animals↗
IDH3-dependent mitochondrial function in stromal fibroblasts suppresses malignant tumor growth.
Malignant solid tumors comprise not only cancer cells but also diverse non-cancerous stromal cells that shape the tumor microenvironment. The tricarboxylic acid (TCA) cycle has an overarching presence in providing substrates needed to drive the electron transport chain and, ultimately, ATP synthesis. However, it remains unclear which stromal cell lineages influence tumor growth through TCA-dependent mitochondrial function, and whether such activities act in a tumor-promoting or tumor-suppressive manner. Isocitrate dehydrogenase 3 (IDH3), a rate-limiting TCA cycle enzyme that generates NADH to support mitochondrial respiration, provides a genetic entry point to interrogate mitochondrial TCA-dependent function in stromal cells. In this study, we established a mouse model in which tamoxifen administration induces CreERT2-dependent knockout of the α subunit of IDH3 (IDH3α) in all somatic cells. Using this model with transplantation of Idh3a-intact murine cancer cells, we found that host Idh3a deficiency accelerated growth of murine MC38 tumors in a cancer cell line-dependent manner. Bone marrow chimera experiments indicated that hematopoietic lineages were not responsible for this phenotype, suggesting a contribution from tissue-resident non-hematopoietic stromal cells that are not replaced by bone marrow transplantation. Single-cell RNA sequencing of human tumor specimens revealed broad IDH3A expression across multiple tumor microenvironment compartments, including fibroblasts. Consistently, in vitro co-culture assays demonstrated that Idh3a-intact, but not Idh3a-KO, fibroblasts suppressed cancer cell proliferation in a contact-dependent manner. Together, these findings identify IDH3α-dependent mitochondrial function in fibroblasts as a critical determinant of tumor progression and suggest that stromal mitochondrial metabolism represents an important axis for modulating tumor behavior.
Cancer↗
Comparative effects of Corynebacterium parvum, Brucella abortus extract, Bacillus Calmette-Guérin, glucan, levamisole, and tilorone with or without cyclophosphamide on tumor growth, macrophage production, and macrophage cytotoxicity in a murine mammary tumor model.
In this laboratory, it has been repeatedly demonstrated (using a murine mammary tumor model) that the combination of cyclophosphamide (CY) and Corynebacterium parvum (CP) is more effective than either agent alone in the control of tumor growth. This paper presents information obtained in our model comparing findings on the effects of CP with a Brucella abortus extract (Bru-Pel; BP) and glucan (GL) on tumor growth. In addition, the influence of those agents as well as bacillus Calmette-Guérin, tilorone, and levamisole on bone marrow macrophage colony production and cytotoxicity is presented. None of the nonspecific stimulating agents (NSSAs) inhibited tumor growth when administered systemically without CY, confirming our previous contention that such immunotherapy alone is likely to be an ineffectual form of treatment. Whereas tumor regression was observed following intratumor CP, neither GL nor BP had such an effect. When used with CY, neither BP nor GL administered ip or intratumorally inhibited tumor growth as effectively as did CP and CY. Inhibition of the growth of a distant tumor as well as the treated tumor occurred following intratumor CP and CY but not following intratumor BP and CY. All of the microbial NSSAs increased macrophage colony production to varying degrees in both normal and tumor-bearing mice. In the latter mice, CP had the most prolonged effect. Levamisole and tilorone failed to increase colony production in normal mice while in tumor-bearing mice the effect was inversely proportional to the amount of agent administered. To some extent, the stimulation of colony production by the NSSAs paralled the degree of tumor inhibition observed when those agents were combined with CY. The cytotoxicity of cultured macrophages could not be related to tumor growth inhibition.
Animals↗
Characteristics of the immature cells involved in T cell-mediated enhancement of syngeneic tumor growth.
Enhancement of tumor growth was observed when non-sensitized thymocytes were injected together with tumor cells into syngeneic mice, although this tumor enhancement was less pronounced than that caused by tumor-sensitized T lymphocytes. The cells within the thymus which are responsible for this tumor enhancement were found to be rapidly dividing and to be absent from the thymus a day after cortisone administration. At a longer time interval the cortison-depleted thymus was repopulated by dividing cells which exhibited tumor-enhancing reactivity. The characteristics of these cells suggest that they are in the early stages of thymic processing. The enhancing thymocytes were sensitive to treatment with the thymic humoral factor which functions in T cell maturation, and their enhancing activity was cancelled by such treatment. These results are compatible with our hypothesis that exposure of immature T cells to a tumor stimulus may lead to tumor enhancement whereas interaction between mature T lymphocytes and tumor cells may be required for tumor inhibition.
Animals↗
Specific enhancement of tumor growth and depression of cell-mediated immunity following sensitization to soluble tumor antigens.
W/Fu rats inoculated s.c. with less than or equal to 5 x 10(7) syngeneic (C58NT)D (Gross virus-positive) lymphoma tumor cells normally develop a palpable tumor which reaches its maximum size (12 to 14 mm) at 6 to 8 days and is subsequently rejected by 10 to 12 days. However, rats previously sensitized with soluble tumor antigens from (C58NT)D cells prior to (C58NT)D tumor inoculation demonstrate a significant enhancement of tumor growth (the tumor reaches up to 26 mm and is rejected by 16 to 18 days). This enhancement persisted in antigen-treated rats that continued to receive soluble antigen after tumor inoculation. The in vivo enhancement coincided with a significant in vitro depression of cell-mediated cytotoxicity [assessed with 51Cr-labeled (C58NT)D target cells and peripheral blood leukocytes]. The observed tumor enhancement was specific, inasmuch as presensitization to either soluble tumor antigens from WR6 (Gross virus-negative) tumor, syngeneic to W/Fu rats, or to soluble antigen from W/Fu spleen cells had no enhancing effect on (C58NT)D tumor growth. Interestingly, sensitization to soluble tumor antigen alone did not elicit detectable cell-mediated immunity, cytotoxic antibody, or serum-blocking activity to the (C58NT)D tumor. We conclude that sensitization to soluble tumor antigens specifically impairs the immune apparatus normally acting in tumor rejection. This impairment appears to act primarily at the induction phase of the immune response.
Animals↗
Detection of anti-tumor antibody in virally induced tumors and its relationship to tumor growth.
The humoral antibody response to virally induced tumors insyngeneic hosts has been studied. The tumors include an SV40 tumor SVT2, the Friend virus-induced leukemias FBL-3 and FLC; and Moloney sarcoma virus-induced tumors. It was found that antitumor antibodies could be detected by the isotopic antiglobulin technique in these tumor systems at a relatively early stage of tumor growth. The kinetics of the antibody response in relation to the status of tumor growth varied between different tumors. In geneumor growth than in the regressors of tumor-free hosts. Reinoculation of tumor cells or recurrence of tumor growth produced elevation of antibody levels (secondary response). The specificity of the antibody reactions also varied in different tumor systems: some antibodies were truly tumor-specific and thus might produce a biological effect on in vivo tumor immunity, whereas others were not. These studies indicated that a sensitive antibody assay could be used for early detection of tumor growth. However, its usefulness in evaluation of the status of tumor growth should be carefully studied in each tumor system.
Animals↗
Monocarboxylate Transporter 2 (MCT2) Reduction Is Associated with Increased Lung Tumor Growth and Alterations in the Immune Microenvironment in a Subcutaneous Tumor Model.
Monocarboxylate transporter 2 (MCT2; SLC16A7) is a high-affinity pyruvate transporter implicated in cancer metabolism. However, its role in lung cancer progression and the tumor microenvironment remains unclear. This study examined the effects of MCT2 reduction on tumor growth and cell-type-specific transcriptional changes within the tumor microenvironment. MCT2 loxP/loxP mice were crossed with mCre-Tg mice, and MCT2 deletion was induced by tamoxifen. Control (CO) mice received vehicle treatment. TC1 cells (100,000 cells/mouse) were injected subcutaneously, and tumors were harvested after 24 days. Single-nucleus RNA sequencing (snRNA-seq) was performed on isolated tumor nuclei (4000 nuclei/sample; n = 3 per group) using the 10x Genomics Chromium platform. Data were processed with Cell Ranger v3.0.2 and Seurat v5.2.1, followed by differential expression and pathway enrichment analyses integrated with macrophage bulk RNA-seq data. Tumors in mice with systemic MCT2 reduction grew significantly faster than those in control mice, demonstrating an association between host MCT2 reduction and increased tumor growth. Transcriptomic analysis generated high-quality profiles from 6864 CO and 10,055 KO nuclei. Clustering identified 12 cellular populations and cell types. MCT2 reduction altered pathways involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid metabolism across multiple populations. Macrophages showed prominent transcriptional changes, including enrichment of MAPK, PI3K-Akt, IgSF-CAM, ECM, and cytokine-cytokine signaling pathways. These findings were supported by macrophage bulk RNA-seq data. Systemic MCT2 reduction was associated with increased tumor growth and broad transcriptional alterations within the tumor micro-environment. Differences in metabolic and immune-related transcriptional programs, particularly in macrophages, identify potential mechanisms associated with tumor progression that warrant further functional investigation.
Animals↗
[Inhibition of tumor growth and metastases in mice with Lewis lung tumors by vitamin A and BCG].
The anti-tumor effect of vitamin A and/or BCG was investigated in Lewis lung tumor system. Tumor growth and lung metastases were significantly suppressed, when tumor cells were mixed with BCG and inoculated subcutaneously into vitamin A-treated animals. Survival time was also prolonged by the same treatment. Vitamin A alone, without BCG, showed no effect on tumor growth, lung metastases or survival time.
Animals↗
Enhancement of tumor growth by peritoneal macrophages of normal and tumor-bearing mice.
The effect of peritoneal macrophages on tumor growth was investigated in an in vivo transfer assay (Winn test). A significant acceleration of tumor appearance was observed in animals injected with tumor cells together with peritoneal exudate cells (PEC) from normal mice, as compared to animals injected with tumor cells alone. Macrophages were shown to be the cells responsible for tumor enhancement. PEC from tumor-bearing mice also caused a strong tumor-enhancing effect in the Winn test. These results indicate that non-activated macrophages can enhance tumor growth in in vivo transfers and raise the question of whether a similar effect takes place in the primary host of a tumor.
Animals↗
Further observations on the inhibition of tumor growth by C. parvum with cyclophosphamide. VII. Effect of treatment prior to primary tumor removal on the growth of distant tumor.
The present investigations were directed toward determining whether primary tumor manipulation prior to its removal is advantageous for the control of metastases and survival. Studies were carried out to ascertain whether 1) there is justification for delaying surgical removal of a primary tumor to permit preoperative administration of cyclophosphamide (CY) and/or C. parvum (CP) and 2) there is an advantage to administering the immunotherapy directly into a primary tumor. After operation, in all investigations, systemic CP and CY was used. Despite the putative similarity of animals, tumors and treatment regimens there was marked variation in response of tumors to therapy. No benefit was derived from administering preoperative immunotherapy alone. When operation was delayed to employ systemic immuno-chemotherapy, a slight improvement in the control of distant tumor was noted. The employment of preoperative intratumor immunotherapy led to a greater prolongation of survival and more inhibition of distant tumor growth than did immediate primary tumor removal or the use of preoperative systemic immunotherapy. The results suggest that there may be an advantage to delaying removal of a primary tumor so that it may be employed in therapeutic strategies directed toward control of metastatic disease.
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Effect of defibrination on tumor growth and response to chemotherapy.
Other investigators have demonstrated fibrin deposition in tumors. Experiments were therefore designed to test whether systemic defibrination would alter tumor growth or tumor response to chemotherapy with cyclophosphamide. Defibrination with Ancrod, a venom extract of Agkistrodon rhodostoma, did not significantly affect tumor sensitivity to chemotherapy. Similarly, defibrination plus fibrinolytic therapy with streptokinase did not affect responsiveness to cyclophosphamide. Long-term defibrination did not affect tumor growth. These results suggest three possible interpretations: (a) the coagulation system may not be important in tumor growth and response to chemotherapy; (b) adequate clearing of fibrin from the tumor was not accomplished in our experiments; or (c) other factors such as platelet deposition may be involved and platelet function was not inhibited by the therapies used in our experiments.
Ancrod↗
Observations on the postoperative tumor growth behavior of certain islet cell tumors.
Over a period of 21 years 39 patients with gastrinoma were surgically treated. Thirty-three patients had total gastrectomy with two postoperative deaths, and 6 patients had a lesser procedure. The postoperative fasting gastrin levels remained elevated and did not always indicate the extent of tumor involvement. Further mobilization of tumor gastrin by provocative infusion of calcium gluceptate, 15 mg/kg of body weight, should be carried out routinely. A hepatic angiogram should be considered when the gastrin levels exceed 1,000 picograms per ml. Chemotherapy consisting of Tubercidin, Streptozotocin and 5-Fluorouracil was given to 5 patients with extensive gastrinoma. All patients felt better and gained from three to 35 pounds in weight. Since 60% of the patients died or have definite evidence of tumor activity it is assumed that the tumor growth was not inhibited and that it is malignant. Approximately 40% of the patients seem to do well despite modest elevations in gastrin levels suggesting that the retained tumor could be considered benign.
Adenoma, Islet Cell↗
Inhibition and promotion of tumor growth by BCG: evidence for stimulation of humoral enhancing factors by BCG.
Effects of pretreatment with BCG, strain Japan, on tumor growth were studied using a transplatable methylcholanthrene (MCA)-induced fibrosarcoma in C3H/He mice. Injection of BCG7 weeks before tumor inoculation at a site distant from the tumor caused a slight inhibition of tumor growth. A low dose of tumor cells did not grow at the BCG-primed site when BCG was injected 7 and 11 weeks before the tumor. When a high dose was inoculated into the BCG-primed site, inhibition of the primary tumor occurred in mice which had received BCG 7 weeks previously, but the number of distant metastases in the popliteal lymph node and the lungs was increased in mice pretreated with BCG at any time. Furthermore, post treatment with BCG at a site distant from the tumor caused promotion of tumor growth. Enhanced antibody formation and suppression of delayed type hypersensitivity (DTH) occurred in tumor-bearing mice. BCG treatment of such mice caused a vigorously enhanced antibody formation and a marked suppression of DTH. The sera from tumor-bearing mice enhanced tumor growth. Tumor growth was suppressed in splenectomized mice. These findings suggested that antibodies against tumor-specific antigens enhanced tumor growth in this system and that BCG treatment of tumor-bearing mice stimulated formation of antibodies probably acting as blocking factors.
Animals↗
Effect of cadmium exposure on primary tumor growth and cell-mediated cytotoxicity in mice bearing MSB sarcomas.
In vivo MSB tumor growth and cell-mediated cytotoxicity (CMC) to MSB tumor cells in vitro were studied in male C57BL/6 mice exposed to 0, 3, 30, or 300 ppm Cd as CdCl2 in their drinking water for 21 weeks prior to and during tumor growth. CMC was assessed on days 5, 12, and 19 post injection with the use of both a 51Cr release assay and a 51Cr post-label assay. Cd exposure significantly inhibited the growth of MSB tumors in vivo and enhanced the levels of CMC in the tumor-bearing hosts. Peak levels of CMC on day 12 post tumor injection were significantly increased in Cd-exposed animals. However, whereas the inhibition of tumor growth was directly dependent on the dose of Cd, the enhancement of CMC was inversely related to dosage. These data suggested that other mechanisms in addition to increased CMC were involved in tumor growth inhibition. Possible factors such as direct inhibition of tumor growth by Cd and decreased serum blocking levels in Cd-exposed animals are discussed.
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