Synergistic Antitumor Interaction of Human Monocyte Chemotactant Protein-1 Gene Transfer and Modulator for Tumor-Infiltrating Macrophages

Purpose. In order to evaluate the possibility of synergistic antitumor gene therapy by the gene delivery of monocyte chemotactant protein-1 (MCP-1/MCAF/IE), the effect of a biological response modulater for macrophages on tumor progression of gene transfected tumor cells was studied. Methods. Cachexia-inducing adenocarcinoma cells (cell line colon 26, clone 20) were transfected with either a control plasmid or MCP-1 cDNA. Results. The production of MCP-1 reached 70-80 ng/ml in vitro when transfectant cells were cultured at a cell density of 1 × 10⁵ cells/ml for 3 days. Transfection of MCP-1 cDNA did not affect the growth ratein vitro. Also, MCP-1-transfectants formed tumors after intra-footpad inoculation similar in size to the parental cells. The number of infiltrating macrophages in the primary tumor of the transfectant rapidly increased from the 3rd to 5th day after inoculation as revealed by immunohistochemical staining using an antibody against mouse macrophages. An earlier, greater, but no longer-lasting increase in tumor-infiltrating macrophages was induced in tumors by MCP-1 transfection was compared to that induced by the parent cells. On the 10th day after the inoculation, the tumor-infiltrating macrophages in mice inoculated MCP-1 transfectants were decreased to a level similar to that of the parent cells. Groups of mice were treated intraperitoneally with LPS at different times after the inoculation. Tumor cells producing high levels of MCP-1 were significantly lysed by macrophages treated with LPS, whereas parental or control transfected cells were not. Conclusions. Combination immunotherapy can provide a rationale for the application of MCP-1 treatment to increase immunological responses to cancer.     

Inhibitory effect of BCG cell-wall skeletons (BCG-CWS) emulsified in squalane on tumor growth and metastasis in mice

The antimetastatic effect of BCG-CWS, which was emulsified in an oil-in-water form with either Drakeol 6VR mineral oil (BCG-CWS/DK) or squalane (BCG-CWS/SQA), on lung metastasis produced by highly metastatic murine tumor cells, Colon26-M3.1 carcinoma cells and B16-BL6 melanoma cells, was investigated in syngeneic mice. An intravenous (i.v.) administration of BCG-CWS (100 mg/mouse) 1 day after tumor inoculation significantly inhibited tumor metastasis of both Colon26-M3.1 carcinoma and B16-BL6 melanoma cells in experimental lung metastasis models. No differences in the antitumor activity of the two oil-based formulations (BCG-CWS/DK and BCG-CWS/SQA) were obverved. However, BCG-CWS/SQA administered through subcutaneous (s.c.) route was shown to be effective only when it was consecutively injected (3 times) after tumor inoculation. An in vivo analysis for tumor-induced angiogenesis showed that a single i.v. administration of BCG-CWS/SQA inhibited the number of tumor-induced blood vessels and suppressed tumor growth. Furthermore, the multiple administration of BCG-CWS/SQA given at on week intervals led to a significant reduction in spontaneous lung metastasis of B16-BL6 melanoma cells in a spontaneous metastasis model. These results suggest that BCG-CWS emulsified with squalane is a potent inhibitory agent of lung metastasis, and that the antimetastatic effect of BCG-CWS is related to the suppression of tumor growth and the inhibition of tumor-induced angiogenesis.     

医用透明质酸钠凝胶对肿瘤生长和转移影响的实验研究

目的 考察医用透明质酸钠凝胶（medical sodium hyaluronate gel,HA）在体外和裸鼠体内对腹、盆腔相关肿瘤生长和转移的影响。方法 利用Hela、CT26和HCT116等3株肿瘤细胞,通过MTT法和Transwell实验分别考察不同浓度HA体外对肿瘤细胞生长和迁移的影响;建立裸鼠结肠原位种植瘤模型,比较瘤块接种4周后不同实验组的瘤块体积和瘤重,考察HA体内对结肠癌HCT116增殖的影响;通过比较接种3周后不同实验组裸鼠的肺和肝脏的肿瘤转移率和转移病灶数,考察HA对结肠癌CT26体内转移的影响。结果 不同浓度HA在体外均未促进Hela、CT26和HCT116细胞的生长和转移,且在5 mg/ml HA浓度下,显示出一定的抑制作用。体内结果显示,HA未促进结肠癌HCT116肿瘤的生长,却显示出明显抑制CT26肿瘤的转移。结论 在本实验条件下,HA在体内、外均未促进腹、盆腔相关肿瘤细胞Hela、CT26和HCT116的生长、迁移和转移。     

Antitumor activity of the Korean Mistletoe Lectin is attributed to activation of macrophages and NK cells

Inhibitory effect of the lectins (KML-C) isolated from Korean mistletoe (KM; Viscum album coloratum) on tumor metastases produced by murine tumor cells (B16-BL6 melanoma, colon 26-M3.1 carcinoma and L5178Y-ML25 lymphoma cells) was investigated in syngeneic mice. An intravenous (i.v.) administration of KML-C (20-50 ng/mouse) 2 days before tumor inoculation significantly inhibited lung metastases of both B16-BL6 and colon 26-M3.1 cells. The prophylactic effect of 50 ng/mouse of KML-C on lung metastasis was almost the same with that of 100 microg/mouse of KM. Treatment with KML-C 1 day after tumor inoculation induced a significant inhibition of not only the experimental lung metastasis induced by B16-BL6 and colon 26-M3.1 cells but also the liver and spleen metastasis of L5178Y-ML25 cells. Furthermore, multiple administration of KML-C given at 3 day-intervals after tumor inoculation led to a significant reduction of lung metastasis and suppression of the growth of B16-BL6 melanoma cells in a spontaneous metastasis model. In an assay for natural killer (NK) cell activity, i.v. administration of KML-C (50 ng/mouse) significantly augmented NK cytotoxicity against Yac-1 tumor cells 2 days after KML-C treatment. In addition, treatment with KML-C (50 ng/mouse) induced tumoricidal activity of peritoneal macrophages against B16-BL6 and 3LL cells. These results suggest that KML-C has an immunomodulating activity to enhance the host defense system against tumors, and that its prophylactic and therapeutic effect on tumor metastasis is associated with the activation of NK cells and macrophages.     

Liposomes modified with YIGSR peptide for tumor targeting

YIGSR peptide anchored sterically stabilized liposomes (YIGSR-SL) were investigated for selective and preferential presentation of carrier contents at angiogenic endothelial cells overexpressing laminin receptors on and around tumor tissue and thus for assessing their targetabilty. In vitro endothelial cell binding of liposomes exhibited 7-fold higher binding of YIGSR-SL to HUVEC in comparison to the nontargeted sterically stabilized liposomes (SL). Spontaneous lung metastasis and angiogenesis assays show that YIGSR peptide anchored liposomes are significantly (P ≤ 0.01) effective in the prevention of lung metastasis and angiogenesis compared to free 5-fluorouracil (5-FU) and SL. YIGSR-SL was very effective in regression of tumors in BALB/c mice bearing B16F10 melanoma cells. Results indicate that YIGSR peptide anchored sterically stabilized liposomes bearing 5-FU are significantly (P ≤ 0.01) active against primary tumor and metastasis than the SL and free drug. Thus, YIGSR peptide anchored sterically stabilized liposomes hold potential of targeted cancer chemotherapeutics.     

Polymeric nanospheres modified with YIGSR peptide for tumor targeting

YIGSR peptide anchored pegylated nanospheres (YIGSR-SN) loaded with 5-fluorouracil (5-FU) were investigated for selective and preferential presentation of carrier contents at angiogenic endothelial cells over-expressing laminin receptors on and around tumor tissue and thus for assessing their targetability. Pegylated nanosphere (SN) without peptide conjugate were used for comparison. The average size of all nanosphere preparations prepared was ～108?nm and maximum drug entrapment was 68.5?±?5.2%. In vitro endothelial cell binding of nanospheres exhibited 8-fold higher binding of YIGSR-SN to HUVEC in comparison to the SN. Spontaneous lung metastasis and angiogenesis assays show that YIGSR peptide anchored nanospheres are significantly (p?≤?0.05) effective in the prevention of lung metastasis and angiogenesis compared to free 5-FU and SN. In therapeutic experiments, 5-FU, SN, and YIGSR-SN were administered intravenously on day 4 at the dose of 10?mg 5-FU/kg body weight to B16F10 tumor bearing BALB/c mice resulting in effective regression of tumors in YIGSR-SN compared with free 5-FU and SN. Results indicate that YIGSR peptide anchored pegylated nanospheres bearing 5-FU are significantly (p?≤?0.05) active against primary tumor and metastasis than the non-targeted pegylated nanospheres and free drug. Thus, YIGSR peptide anchored pegylated nanospheres hold potential of targeted cancer chemotherapeutics.     

Differential Effect of Taxol in Rat Primary and Metastatic Prostate Tumors: Site-Dependent Pharmacodynamics

Purpose. This study compared the sensitivity of rat prostate MAT-LyLu primary and lymph node metastatic tumors to taxol. Methods. Tumors were established by subcutaneous implantation of tumor cells in a hind leg (primary site) of male Copenhagen rats. Lymph node metastases were used for serial transplantation. Eleven pairs of primary and metastatic tumors between the sixth and twentieth generations were harvested and maintained as 3-dimensional histocultures. The effects of taxol (24 hr treatment at 1 nM to 10 µM) were measured by the appearance of apoptotic cells, and by the inhibition of DNA precursor (thymidine) incorporation. To determine the basis of differential sensitivity of primary and metastatic tumors to the DNA inhibition, we examined the expression of multidrug resistance p-glycoprotein (Pgp) and the accumulation of ³H-taxol after 24 hr exposure and the retention after a 48 hr washout period. Results. The fraction of apoptotic cells increased linearly with the logarithm of taxol concentration to a maximal value of 25%; the concentration-response curves for primary and metastatic tumors were superimposable. Taxol produced a sigmoidal, concentration-dependent inhibition of thymidine incorporation; the maximal inhibition of ~40% was reached at 0.1 and 1 µM for primary and metastatic tumors, respectively. Within the primary or metastatic subgroups, the IC₃₀ (drug concentration that produced a 30% inhibition of DNA synthesis) among consecutive generations varied by < 5 fold, but the primary tumor consistently showed a lower IC₃₀ than the daughter or the parent metastatic tumor (mean, 20-fold; median, 15-fold; range, 6- to 56-fold). The finding that the lower drug sensitivity in metastatic tumors was not exhibited in its daughter primary tumor but was regained in its daughter metastatic tumors suggests that the chemoresistant phenotype is maintained only in lymph nodes and not in the primary site. There were no differences in the Pgp status (neither tumor expressed Pgp), accumulation and retention of taxol in primary and metastatic tumors. Conclusions. Taxol induced apoptosis and inhibited DNA synthesis in the rat MAT-LyLu primary and lymph node metastatic tumors. The apoptotic effect was not different among the two tumors, whereas the primary tumor was more sensitive to the inhibition of DNA synthesis. The differential sensitivity of the two tumors to the DNA effect is not associated with a difference in Pgp expression, drug accumulation nor drug retention, and appears to be associated with changes that are linked to lymph node metastasis.     

Relationship between primary tumor volume and lung metastasis in Lewis lung carcinoma (1). Assay for time course of development of metastasis

Relationship between primary tumor volume and development of lung metastases was investigated in Lewis lung carcinoma in male C57BL/6 mice. Tumor cells (1-3 X 10(5] were injected into the muscle of the right hind legs and growth curves of primary tumors were obtained. The time course of development of metastases was determined from the size of lung colonies at autopsy by using growth rate of lung colonies. The first development of metastasis was 4 to 7 days after injection. The incidence of metastases increased as a function of time and was presented by Gompertz function as in primary tumor volume. Therefore, a linear relationship was found to exist between the incidence of metastases and the primary tumor volume. This assay is considered to be useful to understand the time course of development of metastases without resection of the primary tumors.     

Relationship between primary tumor volume and lung metastasis in Lewis lung carcinoma (II). Tumor bed effect

The incidence of lung metastases from tumors which had the tumor bed effect (TBE) was investigated in Lewis lung carcinoma in male C57BL/6 mice. Tumor cells (1-3 x 10(5] were injected into the muscle of the right hind legs which had been locally irradiated with 15 Gy of gamma rays 1 hr or 1, 4, 7, 10, or 14 days previously. The latent periods for tumor appearance were almost the same as in the controls. Compared to the controls, growth delays were observed from about 7 days after tumor cell injection. For metastasis from tumors which had the TBE, although the first development of metastasis was not different from the controls, the total number of metastases was reduced. The incidence of metastases varied according to growth of the primary tumor. The correlation between the primary tumor volume and the incidence of metastases also showed a linear relation, as in the controls. These results indicate that metastasis from tumors growing in pre-irradiated sites depended on the TBE of the primary tumors.     

Liposomes Modified with Cyclic RGD Peptide for Tumor Targeting

Cyclic RGD peptide anchored sterically stabilized liposomes (RGD-SL) were investigated for selective and preferential presentation of carrier contents at angiogenic endothelial cells overexpressing α_vβ₃ integrins on and around tumor tissue and thus for assessing their targetabilty. Liposomes were prepared using distearoylphosphatidylcholine (DSPC), cholesterol and distearoylphosphatidylethanolamine–polyethyleneglycol–RGD peptide conjugate (DSPE–PEG–RGD) in a molar ratio 56:39:5. The control RAD peptide anchored sterically stabilized liposomes (RAD-SL) and liposome with 5 mol% PEG (SL) without peptide conjugate which had similar lipid composition were used for comparison. The average size of all liposome preparations prepared was approximately 105 nm and maximum drug entrapment was 10.2±1.1%. In vitro endothelial cell binding of liposomes exhibited 7-fold higher binding of RGD-SL to HUVEC in comparison to the SL and RAD-SL. Spontaneous lung metastasis and angiogenesis assays show that RGD peptide anchored liposomes are significantly (p<0.01) effective in the prevention of lung metastasis and angiogenesis compared to free 5-FU, SL and RAD-SL. In therapeutic experiments, 5-FU, SL, RGD-SL and RAD-SL were administered intravenously on day 4 at the dose of 10 mg 5-FU/kg body weight to B16F10 tumor bearing BALB/c mice resulting in effective regression of tumors compared with free 5-FU, SL and RAD-SL. Results indicate that cyclic RGD peptide anchored sterically stabilized liposomes bearing 5-FU are significantly (p<0.01) active against primary tumor and metastasis than the non-targeted sterically stabilized liposomes and free drug. Thus cyclic RGD peptide anchored sterically stabilized liposomes hold potential of targeted cancer chemotherapeutics.     

An investigation of the effect of sorafenib on tumour growth and recurrence after liver cancer resection in nude mice independent of phosphorylated extracellular signal-regulated kinase levels

Objective: The goal of this study is to investigate the effects of sorafenib on tumor growth, recurrence and metastasis after curative resection of liver cancer.

Research methods: SMMC-7721 and HCCLM3 liver tumors, each with different metastatic potential and basal phosphorylated extracellular signal-regulated kinase (pERK) levels, were orthotopically implanted into 56 nude mice. Mice were divided into a treatment sub study and a prevention sub study.

Results: In the treatment sub study, tumor volumes in the high pERK-expressing HCCLM3 model were 2.58 ± 0.83 and 0.38 ± 0.09 cm³ without and with sorafenib, respectively (p < 0.001). The corresponding volumes in the low pERK-expressing SMMC-7721 model were 1.36 ± 0.24 and 0.24 ± 0.14 cm³ (p < 0.001), respectively. Sorafenib inhibited HCCLM3 cell proliferation and decreased tumor angiogenesis, but did not inhibit proliferation in the SMMC-7721 model. In the prevention sub study, intrahepatic recurrent tumor volumes were 1.96 ± 0.45 and 0.18 ± 0.24 cm³ (p < 0.001); lung metastasis frequencies were 100 and 0% (p = 0.005); and lifespans were 36 ± 3 and 46 ± 5 days (p = 0.002) in the control and sorafenib subgroups, respectively.

Conclusions: Sorafenib inhibits tumor growth and prevents metastatic recurrence after resection of hepatocellular carcinoma in nude mice. The effect of sorafenib does not exclusively depend on high levels of pERK in tumors.     

Antimetastatic activities of pegylated liposomal doxorubicin in a murine metastatic lung cancer model

To determine whether pegylated liposomal doxorubicin (PLD) could control the metastasis beyond primary tumor, the efficacy of PLD was evaluated in terms of metastatic growth inhibition and increasing life span in a murine lung metastasis model. As early as 20 days after C57BL/6 mice were inoculated with 2 × 10⁶ murine Lewis lung carcinoma cells into the right legs, metastases could be observed in the lungs. Comparing the metastatic status of the PLD treatment conducted one day with one week after the tumor implantation, pathological study of the metastasis in the lungs indicated that without the removal of primary tumor, PLD could prevent metastasis by suppressing the growth of primary tumor. To evaluate the direct antimetastasis ability of PLD with clinical relevance, a surgery was performed to resect the tumor-bearing limb. The treatment was started 3 days after the amputation with free doxorubicin or PLD. In this therapeutic model, PLD targeted directly to the metastasis in the lungs, which resulted in substantially longer survival time than free doxorubicin. Despite the superiority of PLD over free doxorubicin in treating pulmonary metastasis, our observation suggested that without the removal of primary tumor, the effect of PLD was only modest, and surgery plus multiple injections of PLD will be the best choice for patients with metastatic disease.     

Reduction of lung metastasis by ImH[trans-RuCl4(DMSO)Im]: mechanism of the selective action investigated on mouse tumors

NAMI-A (imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate, ImH[trans-RuCl4(DMSO)Im]) is a new ruthenium compound active against lung metastasis of solid metastasizing tumors. We have tested this compound in mice with Lewis lung carcinoma or MCa mammary carcinoma in order to compare the effects on primary tumor and lung metastases with possible alterations of cell cycle distribution of tumor cells. We have also investigated whether there were unequal tissue accumulations of the compound itself at different dose levels ranging from 17.5 to 70 mg/kg/day given for six consecutive days. NAMI-A caused a reduction of metastasis weight larger than that of metastasis number; we explain this finding as the capacity of NAMI-A to selectively interfere with the growth of metastases already settled in the lungs. However, this specificity is not simply related to a larger concentration of NAMI-A in the lungs than in other tissues. Following i.p. treatment, NAMI-A rapidly disappeared from the peritoneal cavity; its low blood concentration may be caused by rapid renal clearance. These data provide further evidence for a selective anti-metastasis effect of the ruthenium complex NAMI-A. The reduction of lung metastasis is followed by a significant prolongation of the host's life-time expectancy, indicating a therapeutic benefit of NAMI-A on lung metastases from solid tumors.     

Immunocompetence status as related to growth progression of mouse MOPC-315 plasmacytoma

The immunocompetence status of mice bearing MOPC-315 plasmacytoma was determined at various days after tumor inoculation. Changes in T and B-cell functions appeared gradually. The allogeneic response of spleen cells from BALB/c tumor-bearing mice against C57BL spleen cells was impaired from the 4th day after the tumor inoculation (nonpalpable tumor stage). The primary antibody response in vitro against SRBC was depressed at 18 days, and the mitogenic response of splenic cells to PHA and to LPS was depressed at 25 days after the tumor inoculation. T cells taken from day 18 tumor-bearing mice partially suppressed the MLR response of normal splenocytes. Mice bearing large MOPC-315 tumors responded less to SRBC immunization than normal, noninoculated mice. The relative percentage of Lyt 1, Lyt 2 and L3T4 T-cell subsets decreased starting from the 11th day after tumor inoculation.     

肝动脉灌注化疗（HAIC）在不可切除结直肠癌肝转移多线治疗耐药后的疗效分析

目的 探讨肝动脉灌注化疗（HAIC）在不可切除结直肠癌肝转移多线治疗耐药后的疗效和安全性。方法 收集本院2020年7月至2021年12月行HAIC治疗不可切除结直肠癌肝转移患者24例,其中既往经过二线治疗的患者14例,经过三线及以上治疗的患者10例,HAIC治疗每3~4周1次,追踪观察患者的客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）、总生存期（OS）和不良反应（AE）,并将影响预后的临床特征进行单因素和多因素分析。结果 24例患者共行56次HAIC治疗,其中2例行1次治疗,14例行2次治疗,6例行3次治疗,2例行4次治疗,ORR为16.7%（4/24）,DCR为62.5%（15/24）,3~4级AE发生率41.7%（10/24）,中位无进展生存期（mPFS）3.4个月,中位生存期（mOS）13.6个月。单因素分析显示,肿瘤数目、肿瘤最大直径、肝外转移及ECOG评分与预后相关（P<0.05）。多因素分析发现,肿瘤数目、肿瘤最大直径、ECOG评分为影响预后的独立危险因素（P<0.05）。结论 HAIC在不可切除结直肠癌肝转移多线治疗耐药后有一定的疗效,不良反应可接受。对于仅有肝内转移,且肿瘤数目较多、肿瘤直径较大、体力状况好的患者能从HAIC中获益;对于存在肝外转移的患者,还需要联合全身静脉化疗。     

人结肠腺癌裸鼠移植瘤转移模型的建立

目的建立稳定的人结肠腺癌裸鼠移植瘤转移模型。方法体外培养人结肠腺癌细胞株LS-174-T,移植入BALB／C裸鼠左胁腹部皮下,观察接种瘤生长及转移情况。结果裸鼠接种人结肠腺癌LS-174-T细胞后3周局部出现肉眼可见的肿物,肿块持续增大至11周后进入平台期。显微镜下观察,第3、5周肺脏、肝脏等均未见转移灶,第7周开始肺部出现小转移灶,以后转移灶数目逐渐增多,其间可见有小血管生成,第11周～13周部分裸鼠出现肝脏转移。结论所建立的结肠腺癌模型稳定性可靠,有助于结肠癌的动物干预实验研究。     

Enhanced cancer metastasis after monocrotaline-induced lung injury

The lung is a target in several models of environmentally induced injury and is also a common site for the growth of metastases from circulating cancer cells. In these experiments, we have tested the hypothesis that pulmonary damage can facilitate the metastasis of cancer to the lung. We have studied the effect of monocrotaline-induced lung injury on the retention and metastasis of intravenously injected Walker carcinosarcoma 256 cells in the lung and the effect of this injury on spontaneous metastasis in animals with intramuscular tumor transplants. Female Wistar rats were given a single subcutaneous injection of monocrotaline (60 mg/kg). The degree of lung injury after monocrotaline was assessed by bronchoalveolar lavage, by histological and ultrastructural examination, and by measurement of right ventricular hypertrophy. To assess the effects of monocrotaline on metastasis, animals were injected iv with 2 X 10(7) [125I]iododeoxyuridine-labeled or unlabeled Walker 256 carcinosarcoma cells at various periods of time (1 day to 20 days) after monocrotaline. The retention of labeled cells was determined by gamma counts of lungs 24 hr after injection. There was a direct correlation between the severity of lung injury and the number of cancer cells retained in the lung 24 hr after injection. Metastasis was quantified by morphometric analysis of histologic sections prepared from lungs 1 week after an injection of unlabeled cells. The median area of lung involved by tumor after iv injection was 39% for rats injected with cancer cells 10 days after monocrotaline vs 3% for controls. In studies on spontaneous metastasis, rats were given an intramuscular injection of Walker 256 cells 5 days after monocrotaline and metastasis was quantified by morphometry 7 days after tumor transplantation. The median tumor burden of animals pretreated with monocrotaline was 37% vs 8% for controls. We conclude that lung injury initiated by monocrotaline can facilitate the spread of the rat Walker 256 carcinosarcoma.     

MACC1 – a novel target for solid cancers

Introduction: The metastatic dissemination of primary tumors is directly linked to patient survival in many tumor entities. The previously undescribed gene metastasis-associated in colon cancer 1 (MACC1) was discovered by genome-wide analyses in colorectal cancer (CRC) tissues. MACC1 is a tumor stage-independent predictor for CRC metastasis linked to metastasis-free survival.

Areas covered: In this review, the discovery of MACC1 is briefly presented. In the following, the overwhelming confirmation of these data is provided supporting MACC1 as a new remarkable biomarker for disease prognosis and prediction of therapy response for CRC and also for a variety of additional forms of solid cancers. Lastly, the potential clinical utility of MACC1 as a target for prevention or restriction of tumor progression and metastasis is envisioned.

Expert opinion: MACC1 has been identified as a prognostic biomarker in a variety of solid cancers. MACC1 correlated with tumor formation and progression, development of metastases and patient survival representing a decisive driver for tumorigenesis and metastasis. MACC1 was also demonstrated to be of predictive value for therapy response. MACC1 is a promising therapeutic target for anti-tumor and anti-metastatic intervention strategies of solid cancers. Its clinical utility, however, must be demonstrated in clinical trials.     

Orthotopic mouse models expressing fluorescent proteins for cancer drug discovery

Importance of the field: Currently used rodent tumor models, including transgenic tumor models, or subcutaneously growing human tumors in immunodeficient mice, do not sufficiently represent clinical cancer, especially with regard to metastasis and drug sensitivity.

Areas covered in this review: To obtain clinically accurate models, we have developed the technique of surgical orthotopic implantation (SOI) to transplant histologically intact fragments of human cancer, including tumors taken directly from the patient, to the corresponding organ of immunodeficient rodents. SOI allows the growth and metastatic potential of the transplanted tumors to be expressed and reflects clinical cancer of all types. Effective drugs can be discovered and evaluated in the SOI models utilizing human tumor cell lines and patient tumors. Visualization of many aspects of cancer initiation and progression in vivo has been achieved with fluorescent proteins. Tumors and metastases in the SOI models that express fluorescent proteins can be visualized noninvasively in intact animals, greatly facilitating drug discovery.

What the reader will gain: This review will provide information on the imageable mouse models of cancer that are clinically relevant, especially regarding metastasis and their use for drug discovery and evaluation.

Take home message: SOI mouse models of cancer reproduce the features of clinical cancer.     

Wf-536 prevents tumor metastasis by inhibiting both tumor motility and angiogenic actions

The signaling pathway of Rho and Rho-associated coiled-coil forming protein kinase (ROCK) is involved in tumor metastasis. In the present study, we investigated the suppressive effect of a novel inhibitor of ROCK, Wf-536 [(+)-(R)-4-(1-Aminoethyl)-N-(4-pyridyl) benzamide monohydrochloride], on spontaneous tumor metastasis in vivo and analyzed its action on tumor cell motility and angiogenesis to clarify its action mechanism. Wf-536 (0.3-3 mg/kg/day) was found to inhibit Lewis lung carcinoma (LLC) metastasis and LLC-induced angiogenesis in orally treated mice; in vitro, it inhibited both invasion and migration by LLC cells and invasion, migration, and formation of capillary-like tubes on Matrigel by endothelial cells, without cytotoxicity or anti-proliferative action in either cell type. We conclude that Wf-536 has tumor anti-metastatic activity which may depend on inhibition of tumor motility and angiogenesis. The findings support its further clinical development as an anti-metastatic agent.