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1.
Kaoru Yoshino Masahiro Tanabe Naomi Ohnuma Hideyo Takahashi 《Clinical & experimental metastasis》1996,14(5):459-465
To elucidate the development of bone metastasis in human neuroblastoma, bone marrow and bone metastases were analysed histologically in a hematogeneous metastasis model of murine neuroblastoma. The bone marrow metastasis occurred initially in the bone marrow sinusoid where tumor cells adhered and extravasated to bone marrow parenchyma, resulting in the formation of nodular lesions in the medullary cavity. The nodular lesions eventually progressed to diffuse lesions segmentally occupying the medullary cavity. During the establishment of the diffuse lesions, tumor cells invaded cancellous bone and/or bone cortex, resulting in bone metastasis. Such nodular or diffuse bone marrow metastatic lesions occurred sporadically in a variety of bones. To improve the results of treatment for neuroblastoma, the characteristics of the bone marrow and the bone metastases demonstrated in this study should be considered in the diagnosis and treatment of this disease. 相似文献
2.
神经母细胞瘤骨髓转移23例临床病理分析 总被引:1,自引:1,他引:1
目的 探讨神经母细胞瘤骨髓转移的临床病理特征.方法 对23例神经母细胞瘤骨髓转移的临床病理资料进行分析,并做光镜观察及免疫组化染色.结果 神经母细胞瘤骨髓转移表现为微小浸润、中度浸润和弥漫浸润三种形式,主要根据骨髓造m组织与肿瘤成分的比例和分布而定,其中微小浸润常需行CgA/NSE免疫组化染色辅助诊断.结论 神经母细胞瘤骨髓转移的诊断需结合临床、光镜及免疫组化,以提高检出率并鉴别于横纹肌肉瘤、骨Ewing肉瘤、淋巴母细胞淋巴瘤/白血病. 相似文献
3.
Henriksson KC Almgren MA Thurlow R Varki NM Chang CL 《Clinical & experimental metastasis》2004,21(6):563-570
Neuroblastoma is the most common extra-cranial solid tumor of infancy and childhood, and majority of patients die from the
metastatic disease. Orthotopic xenograft mouse models are valuable tools for improving our understanding and control of neuroblastoma
metastasis, because they readily represent genetic diversity and allow spontaneous metastasis. Intra-adrenal injection is
commonly used for establishing the orthotopic animal models since human neuroblastoma frequently originates in the adrenal
gland. However, it is unclear whether the metastatic potential of neuroblastoma can be reliably determined in adrenally-injected
mice because their gland size is so small. In this study, we developed and characterized a fluorescent orthotopic xenograft
animal model of NB69-derived human neuroblastoma. By comparing animals receiving adrenal injection and adrenal overlay, with
the latter mimicking injection spillover, we found that the metastatic potential of neuroblastoma can be reliably determined
in animal lungs. Furthermore, the lung metastasis can be genetically modulated in these animals. The results also show that
the expression of Renillagreen fluorescent protein (GFP) was exceptionally stable in NB69 cells, allowing rapid and sensitive detection of lung metastases
at the macroscopic level. Additional features of our model include 100 tumor take, a 1-week tumor latency, resemblance to
tumor behaviors in neuroblastoma patients, and the ability to monitor the expression of a gene of interest with GFP. This
animal model of human neuroblastoma will be useful for studying genes involved in the metastatic process and for evaluating
anti-metastasis agents in pre-clinical trials.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
4.
《Growth factors (Chur, Switzerland)》2013,31(4):327-338
AbstractRetroviral-mediated gene transfer was employed to introduce an IL-1α cDNA into an IL-6-dependent murine B-cell line. Bone marrow metastases and bone lesions were frequently observed following intravenous injection of these B cells into syngeneic mice. Because the retroviral vector also contained the neomycin phosphotransferase gene, metastatic cells could be easily recovered from bone marrow by addition of G418 to the culture medium. Interestingly, the metastatic B cells were found to retain their IL-6 dependency through several transplant generations. By comparison, intravenous injection of autonomously-growing B-cell lines generated in vitro by retroviral introduction of an IL-6 cDNA rarely resulted in bone marrow metastases. These results demonstrate that abrogation of growth factor dependency is neither necessary nor sufficient for the in vivo growth and dissemination of tumor cells in this experimental system. It is proposed that the increased metastasis of the IL-1 α-producing B-cells to bone marrow is due to alterations in cell adhesion molecules. The B-cell bone marrow metastasis model described here may be useful for studies of bone marrow homing and for evaluation of therapeutic regimens for multiple myeloma. 相似文献
5.
We have developed a series of novel mammary epithelial cell lines from tumors arising in strain 129 mice, with the ultimate
goal of evaluating the role of host factors in the development of bone metastases. Mammary tumors were induced in mice with
subcutaneously implanted medroxyprogesterone acetate (MPA) pellets followed by administration of DMBA by oral gavage. Mammary
tumor development was efficient in the 129 strain and was independent of osteopontin (OPN) expression. Epithelial cell lines
were isolated from these tumors; surprisingly, these cells did not form tumors upon inoculation into the mammary fat pad of
syngeneic mice, even when MPA was present. One OPN-deficient cell line was selected for further study; full transformation
of these cells required expression of both polyoma middle T and activated ras. These doubly transfected cells, 1029 GP+Er3,
grew in soft agar, and formed hormone-independent tumors efficiently in the mammary fat pad that spontaneously metastasized
to several soft tissue sites but not to the bone. Derivatives of these cells were isolated from tumors arising in the fat
pad and from a lung metastasis (r3T and r3L, respectively): these cells formed tumors more rapidly in the fat pad than the
parental GP+Er3 cells. Upon left ventricle injection, the r3T and r3L cells formed osteolytic bone metastases in 129 mice,
with few metastases seen in other organs. These tumors filled the marrow cavity, and caused extensive destruction of both
cortical and trabecular bone. Intriguingly, in an alternative syngeneic host, (129× C57Bl/6) F1, osteolytic bone metastases
were not seen on x-ray; instead extensive liver metastasis was present in these mice, indicating that genetic factors in these
two strains regulate tumor cell homing and distribution during metastasis. These cell lines provide an important new tool
in the study of bone metastasis, particularly in elucidating the role of host factors in the development of these lesions,
as the 129 mouse strain is frequently used for genetic manipulations in the mouse.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
6.
A murine model of bone marrow micrometastasis in breast cancer 总被引:3,自引:0,他引:3
Murphy BO Joshi S Kessinger A Reed E Sharp JG 《Clinical & experimental metastasis》2002,19(7):561-569
Bone marrow (BM) is one of the most common sites and often the first clinical indication of metastatic progression of breast
cancer. Multivariate analyses have shown that the presence of cytokeratin positive tumor cells in the marrow of women with
newly diagnosed stage I, II or III breast cancer is an independent predictor of survival. The objective of this study was
to develop an orthotopic model of spontaneous BM metastasis to facilitate studies of this process. A murine mammary adenocarcinoma
cell line, Clone 66, was transduced with the neomycin resistance gene (Cl66neo) and injected orthotopically into female Balb/c mice. Polymerase chain reaction (PCR) for the neo gene performed on BM cells
harvested from tumor bearing mice demonstrated as few as 102 injected tumor cells produced BM micrometastases at 4 weeks post-injection. Small foci of tumor cells were identified in
the mammary fatpad (mfp) without gross evidence of primary tumors. Higher doses of tumor cells produced BM micrometastases,
detectable by PCR, at one week post-injection. Constructs containing green fluorescent protein (GFP) and the neomycin resistance
gene (neo) were also transduced into Clone 66 cells (Cl66-GFPneo) and injected into the mfp. GFP transduced tumor cells were identified in multiple tissues in addition to BM by flow cytometric
analysis (FACS) but less 13% of the animals developed gross metastases. This model is a clinically relevant tool for the analysis
of organ specificity of metastasis.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
7.
MDA-MB-435 human breast carcinoma metastasis to bone 总被引:3,自引:0,他引:3
Breast cancer metastasizes to bone with high frequency and incidence. However, studies of breast cancer metastasis to bone
have been limited by two factors. First, the number of models that colonize bone are limited. Second, detection of bone metastases
is too insensitive or too laborious for routine, large-scale studies or for studying the earliest steps in bone colonization.
To partially alleviate these problems, the highly metastatic MDA-MB-435 (435) human breast carcinoma cell line was engineered
to constitutively express enhanced green fluorescent protein (GFP). While 435GFP cells did not form femoral metastases following orthotopic or intravenous injections, they produced widespread osteolytic
skeletal metastases following injection into the left ventricle of the heart. All mice developed at least one femur metastasis
as well as a mandibular metastasis. As in humans, osseous metastases localized predominantly to trabecular regions, especially
proximal and distal femur, proximal tibia, proximal humerus and lumbar vertebrae. 435GFP cells also developed metastases in adrenal glands, brain and ovary following intracardiac injection, suggesting that this
model may also be useful for studying organotropism to other tissues as well. Additionally, GFP-tagging permitted detection
of single cells and microscopic metastases in bone at early time points following arrival and at stages of proliferation prior
to coalescence of individual metastases.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
8.
E.W. Thompson V. Sung M. Lavigne K. Baumann N. Azumi A.D. Aaron R. Clarke 《Clinical & experimental metastasis》1999,17(3):193-204
The LCC15-MB cell line was established from a femoral bone metastasis that arose in a 29-year-old woman initially diagnosed with an infiltrating ductal mammary adenocarcinoma. The tumor had a relatively high (8%) S-phase fraction and 1/23 positive lymph nodes (LN). Both the primary tumor and LN metastasis were positive for estrogen receptor (ER) and progesterone receptor (PgR), but lacked erbB2 expression. Approximately one year later, the patient presented with a 0.8 cm comedo-type intraductal mammary adenocarcinoma in the left breast that was negative for ER and PgR, but positive for erbB2. Thirty-five months after the initial diagnosis she was treated for acute skeletal metastasis, and stabilized with a hip replacement. At this time, tumor cells were removed from surplus involved bone, inoculated into cell culture, and developed into the LCC15-MB cell line. The bone metastasis was a poorly differentiated adenocarcinoma lacking ER, PgR, and erbB2, characteristics shared by the LCC15-MB cells, although ER can be re-expressed by treatment of the LCC15-MB cells for 5 days with 75 M 5-aza-2-deoxycytidine. The LCC15-MB cell line is tumorigenic when implanted subcutaneously in NCr nu/nu mice and produces long-bone metastases after intracardiac injection. Although the bone metastasis from which the LCC15-MB cell line was derived lacked vimentin (VIM) expression, the original primary tumor and lymph node metastasis were strongly VIM positive, as are LCC15-MB cells in vitro and in nude mice. The karyotype and isozyme profiles of LCC15-MB cells are consistent with its origin from a human female, with most chromosome counts in the hypertriploid range. Thirty-two marker chromosomes are present. These cells provide an in vitro/in vivo model in which to study the inter-relationships between ER, VIM, and bone metastasis in human breast cancer. 相似文献
9.
Amirkhosravi Ali Warnes Gary Biggerstaff John Malik Zaiba May Kelly Francis John L. 《Clinical & experimental metastasis》1997,15(4):453-461
Pentoxifylline (PTX) has been reported to have both direct and indirect anti-tumor effects in experimental tumor models. We studied the effect of PTX on (1) the proliferation of Neuro2a mouse neuroblastoma cells in vitro and in vivo, (2) spontaneous and experimental metastasis, (3) tumor cell membrane fluidity and (4) adhesion to a fibronectin-coated surface. PTX significantly reduced the proliferation of Neuro2a cells in vitro as determined by DNA measurement (P< 0.01) and total cell count (P< 0.02). In vivo, PTX reduced the growth of subcutaneously transplanted primary tumors in syngeneic A/J mice (P< 0.01; n=15). All seven animals (100%) receiving intravenous tumor cells developed extensive liver metastasis. In contrast, only 1/11 (9%) of animals pre-treated with oral PTX and injected with PTX-treated cells developed liver metastases. Of five mice receiving PTX-treated cells without oral pretreatment of PTX, two out of five (40%) developed liver metastases. There was a slight, but not significant (P=0.08) increase in both experimental and spontaneous lung metastases formation in PTX-treated animals. However, tumor nodule formation on the lung surface was inefficient. PTX also increased membrane fluidity of the Neuro2a cells and significantly decreased tumor cell adhesion to fibronectin-coated microtiter wells (P< 0.01). We conclude that PTX has a cytostatic effect on the Neuro2a mouse neuroblastoma and exerts an anti-tumor effect on liver metastases following intravenous administration of neuroblastoma cells. Whether these results are directly related to the changes in membrane properties caused by pentoxifylline remains to be established. 相似文献
10.
Bone marrow metastatic myeloma cells promote osteoclastogenesis through RANKL on endothelial cells 总被引:3,自引:0,他引:3
We have been using the B9/BM1 murine bone marrow metastasis model to study the function of adhesion molecules in the cell-cell
interactions and transendothelial migration, necessary for tumor metastasis. The cell surface phenotype of these cells, which
colonize vertebral and femoral marrow after intravenous injection, shows great similarity to that of human myeloma cells.
In the present study, we investigated the interaction between B9/BM1 cells and osteoclasts, which likely support tumor metastasis
in bone marrow. We found that co-culturing B9/BM1 cells and bone marrow-derived endothelial cells (BMECs) in the presence
of vitamin D3 and M-CSF promoted differentiation of primary osteoclast progenitors to osteoclasts (detected by TRAP staining), and that
this effect was blocked when BMECs were separated from the other cells by a porous polycarbonate membrane. Flow cytometry
analysis showed that BMECs expressed RANKL (receptor activator of NF-κB ligand) protein on their surface, and that this expression
was up-regulated by co-culture with B9/BM1 cells. Accordingly, RT-PCR showed expression of RANKL mRNA also to be up-regulated
in BMECs co-cultured with B9/BM1 cells. Addition of OPG (osteoprotegerin, a decoy RANKL receptor) to the co-culture system
completely blocked osteoclast induction, as did addition of anti-CD44 antibody. Furthermore, intravenous injection of B9/BM1
cells substantially increased the numbers of TRAP-positive osteoclasts detected in mice in vivo. Taken together, these findings suggest that B9/BM1 myeloma cells act via CD44 to stimulate RANKL expression on BMECs, which
in turn physically interact with osteoclast progenitors to promote their differentiation to osteoclasts and metastasis in
bone marrow.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
11.
Zhang H Yano S Miki T Goto H Kanematsu T Muguruma H Uehara H Sone S 《Clinical & experimental metastasis》2003,20(2):153-159
In the present study, we examined the effects of a newly developed bisphosphonate, minodronate (YM529), on osteolytic bone
metastasis caused by lung cancer. Human small-cell lung cancer (SBC-5) cells, injected intravenously into natural killer cell-depleted
SCID mice, produced radiologically detectable bone metastasis by day 18 and macroscopically visible visceral metastases (lung,
liver, kidney, systemic lymph node) by day 35. Prophylactic treatment with YM529 on day 1 significantly inhibited the formation
of osteolytic bone metastasis evaluated on X-ray photographs in a dose-dependent manner. In addition, treatment with YM529
after establishment of bone metastasis (on day 21) also inhibited bone metastasis, although the treatment was more effective
when started earlier. Single administration was as effective as repeated treatment, suggesting a sustained inhibitory effect
of YM529 on bone metastasis. YM529 reduced the number of osteoclasts in the bone metastatic lesions in vivo, but had no effect on the proliferation or cytokine production of SBC-5 cells in vitro. These results suggest that YM529 is a potent inhibitor of bone metastasis of human lung cancer, probably by suppressing
osteoclastic bone resorption. In contrast, treatment with YM529 had no effect on visceral metastasis, even if started on day
1, and did not prolong the survival of the mice. Therefore, development of a combined modality is necessary for prolonging
the survival of small-cell lung cancer patients with multiple-organ metastasis.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
12.
Gauvain KM Garbow JR Song SK Hirbe AC Weilbaecher K 《Clinical & experimental metastasis》2005,22(5):403-411
Bone metastasis causes significant morbidity in cancer patients, including bone pain, pathologic fractures, nerve compression
syndrome, and hypercalcemia. Animal models are utilized to study the pathogenesis of skeletal metastases and to evaluate potential
therapeutic agents. Previously published methods for imaging bone metastasis in rodent models have focused on identifying
advanced stage metastasis using simple X-rays. Here we report MRI as a method for detecting early bone metastases in mouse
models in vivo. B16 mouse melanoma cells were injected into the left cardiac ventricle of C57BL/6 mice and magnetic resonance (MR) images
were obtained of the left leg following the development of metastatic disease, when tumor associated bone destruction was
histologically present but not visible by X-ray. T1 and T2 relaxation times of bone marrow were measured in healthy control
mice and B16 melanoma tumor-bearing mice. Mean T2 values for normal marrow were 28 ms (SD 5) and for diseased bone marrow
were 41 ms (SD 3). T2 relaxation time of diseased bone marrow is significantly longer than that of normal bone marrow (P < 0.0001) and can be used as a marker of early bone metastases. These studies demonstrate that MR imaging can detect bone
marrow metastases in small animals prior to development of cortical bone loss identified by X-ray. 相似文献
13.
BACKGROUND: The accurate assessment of metastases is an essential component of the staging process for children with neuroblastoma. AIMS: To study the sensitivity of the immunohistochemical marker neuroblastoma 84 (NB84) for the detection of bone marrow infiltrates in children with stage 4 neuroblastoma. METHODS: Primary tumour specimens, bone marrow trephine biopsy specimens and lymph node metastases, taken from children with neuroblastoma that had metastasised to bone marrow, were assessed with a panel of commonly used immunohistochemical markers for neuroblastoma. A comparison was drawn between the sensitivity of the marker NB84 for primary tumours and for bone marrow metastases. RESULTS: NB84 immunolabelled all pre-chemotherapy and post-chemotherapy (n = 24) paired primary tumour specimens, as well as each of a further 20, unpaired, pre-chemotherapy primary tumour specimens. It also labelled all (n = 4) lymph node metastases. Immunolabelling of bone marrow trephine biopsy specimens (21/33) was less sensitive. Of 16 primary tumour specimens with a paired bone marrow trephine biopsy specimen, all immunostained positive, whereas only 62.5% of bone marrow biopsy specimens immunostained positive for NB84. The number of bone marrow biopsy specimens immunostaining for NB84 was significantly lower than the number of paired primary tumour specimens (p = 0.041). CONCLUSIONS: NB84 remains a useful marker for the diagnosis of neuroblastoma in primary tumour specimens, but not for neuroblastoma that has metastasised to bone marrow. 相似文献
14.
Shaker MR Yang G Timme TL Park SH Kadmon D Ren C Ji X Lee HM Sehgal I Anzano M Sporn MB Thompson TC 《Clinical & experimental metastasis》2000,18(5):429-438
The effects of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on prostate cancer metastasis in vivo were evaluated in the mouse prostate reconstitution (MPR) model. MPRs were produced by infection of either heterozygous (+/−)
or nullizygous (−/−) p53-mutant fetal prostatic epithelial cells with the recombinant retrovirus Zipras/myc 9. Previous studies
have documented that loss of p53 function potentiates metastasis in this model system. MPRs were grafted into homozygous (+/+)
p53 male mice, fed a 4-HPR containing diet or a control diet and maintained until the status of tumor progression dictated
sacrifice. Under these experimental conditions, treatment with 4-HPR did not have a significant effect on primary tumor wet
weight for either p53 +/− or p53 −/− MPRs. For, p53 +/− MPRs the animals fed the 4-HPR diet had a slight improvement in survival
and a significant reduction in the number of mesenteric metastases (P=0.0477, t-test). Notably, in p53 +/− MPRs the incidence of metastasis to lumbar spine and sternum was 92% in the control animals compared
to 54% in the 4-HPR treated animals (P=0.035, χ2-test). In p53 −/− MPRs there was a trend toward a reduction in the number of soft tissue metastases to lung and liver in
the 4-HPR group relative to the control diet group and a statistically significant reduction in the incidence of metastasis
to bone was demonstrated in that 50% of control animals versus 30% of 4-HPR treated p53 −/− animals harbored bone metastases
(P=0<0.05, χ2-test). Cell lines were established from portions of the primary tumor and from selected metastatic deposits in each experimental
group. Clonal analysis, by retroviral integration pattern, indicated increased clonal diversity in both the primary tumors
and metastasis-derived cell lines from 4-HPR treated animals relative to the control animals. In vitro treatment with 4-HPR did not reveal discriminating differences between cell lines derived from primary tumors and bone metastases
or control and treatment groups in regard to growth arrest or apoptotic responses. Overall these studies indicate limited
anti-tumor and anti-metastatic activity in this highly aggressive in vivo mouse model of prostate cancer, yet 4-HPR treatment significantly suppressed the development of bone metastases in p53 +/−
and p53 −/− MPRs revealing a novel and potentially clinically useful activity of this retinoid.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
15.
Stage IV-S neuroblastoma, characterized by a primary tumor plus disseminated tumors in liver, skin and bone marrow, has a favorable clinical prognosis when compared to metastatic Stage IV neuroblastoma. This favorable outcome also characterized mice receiving tumor transplants to these "IV-S" sites. We report the testing of the hypothesis that enhanced anti-tumor immunity in "IV-S" site neuroblastoma recipients explains this improved survival. A million murine C1300 neuroblastoma cells were inoculated into 256 A/J mice to either "IV-S" sites of skin, liver, peritoneal cavity, or to the disseminated stage "IV" sites of subcutaneous tissue, muscle, kidney and lung. After 21 and 28 days of tumor growth, spleen cells from tumor bearing mice were harvested and analyzed by a 51 Cr release lymphocytotoxicity assay. Cytotoxic T cell activity was consistently higher at day 28 than day 21. In the liver and in the peritoneal cavity, cytotoxic T cell activity was higher than in other organs, and at day 28 these values were significantly higher than Stage "IV" sites. On the other hand, skin is not a immunologically privileged site in vivo study. 相似文献
16.
Regression of bone metastases following adoptive transfer of anti-CD3-activated and IL-2-expanded tumor vaccine draining lymph node cells 总被引:2,自引:0,他引:2
As many as 80% of patients with breast, prostate, or lung cancer develop bone metastases during the course of their illness. However, thus far, no attempts have been made to explore the potential value of adoptive immunotherapy with antigen-specific T lymphocytes specifically for the treatment of skeletal metastases. Here, we demonstrate tumor regression in a preclinical model of bone metastases from the murine B16BL6 melanoma following adoptive transfer of effector T lymphocytes obtained from tumor vaccine draining lymph nodes. The antitumor effect required transfer of high number of effector cells, which was dependent on CD8+ cells as demonstrated by in vivo depletion of different T cell subsets, and was magnified if effector cells were administered to the arterial supply of the bone/bone marrow. Using flow cytometric analysis, CFSE-labelled Thy1.1+ donor T cells were isolated from the bone marrow of tumor-bearing mice at 24 h and 6 days following adoptive transfer. At the latter time point cell division of the transferred effector cells was detectable. Currently, no curative treatment is known for skeletal metastases in clinical practice. Considering the promising early findings in the present study, further studies exploring the therapeutic potential of adoptive immunotherapy for metastatic disease to the skeleton are warranted. 相似文献
17.
Stimulation of bone resorption results in a selective increase in the growth rate of spontaneously metastatic Walker 256 cancer cells in bone 总被引:2,自引:0,他引:2
Paul J. Kostenuik Gurmit Singh Kaye L. Suyama F. William Orr 《Clinical & experimental metastasis》1992,10(6):411-418
To test the hypothesis that bone metastasis is related to the rate of bone remodeling, we have examined the effect of enhanced bone resorption on the growth of spontaneously metastatic Walker 256 (W256) cancer cells. Bone resorption was stimulated in male Fischer rats by injecting Rice H-500 Leydig tumor cells subcutaneously. The resorptive response of the skeleton was confirmed in a pilot study by evaluating parameters of bone morphometry after 4, 7 and 10 days of tumor burden. The distal femoral epiphyses had 35 ± 10% more osteoclast surface, 83 ± 11% less osteoblast surface, and 46 ± 5% less trabecular bone after 10 days of tumor burden, compared to non-tumor-bearing controls. To evaluate the effect of Leydig tumor-induced bone resorption on the growth response of W256 cells, 20 rats were injected intramuscularly with 2 × 107 W256 cells, and 20 rats were vehicle-injected. Two days later, 10 rats from each group were injected subcutaneously with Leydig tumor cells. Twelve days after W256/vehicle injection, rats were injected with [3H]thymidine, killed 2 h later, and their femurs, liver, lungs and kidneys were processed for histology. In rats injected with Leydig tumor cells only, enhanced bone resorption was confirmed by a 40 ± 4% increase in serum calcium concentration, a 48 ± 8% decrease in trabecular bone content, and a 72 ± 15% decrease in osteoblast surface, compared with non-tumor-bearing rats. Metastatic W256 cells adjacent to trabecular bone in Leydig tumor-bearing rats had a 56 ± 18% greater relative [3H]thymidine labeling index (TdR) than did W256 cells in the bones of non-Leydig tumor-bearing rats. The TdRs of W256 cells in the liver, lungs, and kidneys were not affected by Leydig tumor burden. In this model, enhanced bone resorption was associated with the selective growth promotion of metastatic W256 cells in bone, suggesting the existence of a bone-derived factor which is mitogenic to W256 cells. 相似文献
18.
Yuichi Takiguchi Takayuki Kuriyama Tadaaki Miyamoto 《Clinical & experimental metastasis》1995,13(3):184-190
A transformed NIH 3T3 fibroblast cell line, CI-e, normally does not produce spontaneous metastasis from subcutaneous or footpad tumors in nude mice. However, pulmonary tumor nodules are formed when more than 1 × 103 cells are injected intravenously into nude mice. Co-injection of 1 × 106 heavily irradiated and inactivated cells increases the clonogenic ability of the viable cells in that tumor colonies then occur with as few as 1 × 102 viable cells. Utilizing the action of these inactivated cells to enhance the lung colonizing ability of a relatively small number of viable tumor cells, we have developed a novel experimental model of spontaneous metastasis. In this model, a footpad tumor of the nude mouse metastasizes to the lungs following intravenous injection of 1 × 106 inactivated cells at a specific time of tumor growth and following tumor foot amputation, whereas no spontaneous metastasis develops without injection of inactivated cells. This model enables us to detect metastatic ability which would otherwise be too low to detect using other assays. In addition, it allows us to evaluate metastatic ability at a specific time point during primary tumor growth, since no metastases can develop during the periods before inactivated cell injection and after tumor amputation. Using this model, we have determined that the metastatic ability of CI-e tumors in the footpad is constant throughout the exponential and stationary growth phases, even though cells isolated from exponentially growing tumors possess a 3.3-fold greater lung colonizing ability following intravenous injection than those from stationary tumors. This new experimental model may be applicable to other tumor cell lines and to other analyses where metastatic ability during a defined interval of tumor growth is of importance. 相似文献
19.
The matrix metalloproteinase inhibitor batimastat inhibits angiogenesis in liver metastases of B16F1 melanoma cells 总被引:8,自引:0,他引:8
Stewart Wylie Ian C. MacDonald Hemanth J. Varghese Eric E. Schmidt Vincent L. Morris Alan C. Groom Ann F. Chambers 《Clinical & experimental metastasis》1999,17(2):111-117
Matrix metalloproteinases (MMPs) have been shown to contribute functionally to tumor metastasis. MMP inhibitors are thus being assessed for clinical utility as anti-metastatic therapeutics. Batimastat (BB-94) is a synthetic MMP inhibitor that has been shown to inhibit tumor growth and metastasis in mice. Here we assessed the ability of batimastat to inhibit liver metastases of murine B16F1 cells, after injection of cells in mice via mesenteric vein to target the liver. We then determined which of the sequential steps in metastasis were affected by batimastat, in order to identify its mechanism of action in vivo. Intravital videomicroscopy was used to assess the effect on extravasation, and a cell accounting procedure was used to determine the effect on initial survival of cells. Stereological quantification of functional blood vessels was used to determine the effect on tumor vascularity, thereby avoiding problems associated with immunohistochemical detection of liver sinusoidal endothelial cells. We found that batimastat (50 mg/kg i.p. 5 h prior to and after cell injection, daily thereafter) resulted in a 23% reduction in mean diameter of liver metastases (equivalent to a 54% reduction in tumor volume), while not reducing the number of metastases. Extravasation of cells from the liver circulation was not affected: at 8, 24 and 48 h after injection of cells, the same proportion of cells had extravasated from treated vs. control mice. Batimastat also did not inhibit early survival of cells. However, batimastat-treated mice had a significantly reduced percentage vascular volume within liver metastases, indicating inhibition of angiogenesis. This study demonstrates in vivo that the mechanism by which batimastat limits growth of B16F1 metastases in liver is not by affecting extravasation, but by inhibiting angiogenesis within metastases. This finding suggests that MMP inhibitors may be appropriate for use in patients with metastatic cells that have already extravasated in secondary sites. 相似文献
20.
Chikao Yasuda Shoei Sakata Sachiro Kakinoki Yoshifumi Takeyama Harumasa Ohyanagi Hitoshi Shiozaki 《Pathophysiology》2010,17(2):149-155
TNP-470 (AGM-1470, O-(chloroacetylcarbamoyl) fumagillol), which strongly inhibits the angiogenesis, is promising as a new drug for tumor dormancy therapy; however, TNP-470 is very unstable in vitro and in vivo. We previously prepared TNP-470 containing microspheres composed of poly (lactic acid) with medium-chain triglyceride, and demonstrated that the microspheres released TNP-470 over the long-term in vitro. The present study was undertaken to evaluate the release profile of TNP-470 in vivo and the inhibitory effect on hepatic metastasis of neuroblastoma. It was found that the microspheres could maintain high levels of TNP-470 in the blood plasma for over 4 weeks in vivo. In addition, hepatic metastasis of neuroblastoma was strongly inhibited at 2 weeks after intraperitoneal injection of the microspheres. Following 2 weeks of treatment, the liver weights of mice injected with TNP-DDS (TNP-DDS (H), and TNP-DDS (L) groups) and those injected with only physiological saline (C-1300 group) after implantation of neuroblastoma cells were 1.18 ± 0.13 g, 1.28 ± 0.10 g, and 2.54 ± 0.97 g, respectively (p < 0.05; C-1300 group compared with the TNP-DDS (H) and the TNP-DDS (L) groups, respectively). It was evident that microspheres containing TNP-470 have an excellent potential for clinical application in tumor dormancy therapy. 相似文献