Altered Biological Potential and Radioresponse of Murine Tumors in Different Microenvironments

이익재,이은정,박효진,김원우,하상준,신유근,성진실 대한암학회 2016 Cancer Research and Treatment Vol.48 No.2

Purpose This study was conducted to evaluate the biological features of murine hepatocarcinoma according to different tumor microenvironmental models and to determine the change in molecular and immunologic responses after radiation. Materials and Methods Tumor models were established in the liver (orthotopic) and thigh (heterotopic) of male C3H/HeN mice. Tumor growth and lung metastasis were assessed in these models. To evaluate the radiation effect, the tumors were irradiated with 10 Gy. Factors associated with tumor microenvironment including vascular endothelial growth factor (VEGF), cyclooxygenase- 2 (COX-2), transforming growth factor beta1 (TGF-!1), CD31, and serum interleukin- 6 (IL-6) were evaluated. Tumor-infiltrating regulatory immune cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) were also analyzed. Results A higher number of lung metastases were observed in the orthotopic tumor model than in the heterotopic tumor model. VEGF, CD31, COX-2, and TGF-!1 expression was more prominent in the orthotopic tumor model than in the heterotopic tumor model. Expression of the angiogenic factor VEGF and key regulatory molecules (TGF-!1 and COX-2) decreased following radiation in the orthotopic tumor model, while the serum IL-6 level increased after radiation. In the orthotopic tumor model, the number of both Tregs and MDSCs in the tumor burden decreased after radiation. Conclusion The orthotopic tumor model showed higher metastatic potential and more aggressive molecular features than the heterotopic tumor model. These findings suggest that the orthotopic tumor mouse model may be more reflective of the tumor microenvironment and suitable for use in the translational research of radiation treatment.

Inhibitory Effects of Dunning Rat Prostate Tumor Fluid on Proliferation of the Metastatic MAT-LyLu Cell Line

Bugan, Ilknur,Altun, Seyhan Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.2

Tumor fluid accumulation occurs in both human cancer and experimental tumor models. Solid tumors show a tendency to tumor fluid accumulation because of their anatomical and physiological features and this may be influenced by molecular factors. Fluid accumulation in the peri-tumor area also occurs in the Dunning model of rat prostate cancer as the tumor grows. In this study, the effects of tumor fluids that were obtained from Dunning prostate tumor-bearing Copenhagen rats on the strongly metastatic MAT-LyLu cell line were investigatedby examining the cell's migration and tumor fluid's toxicity and the kinetic parameters such as cell proliferation, mitotic index, and labelling index. In this research, tumor fluids were obtained from rats injected with $2{\times}10^5$ MAT-LyLu cells and treated with saline solution, and 200 nM tetrodotoxin (TTX), highly specific sodium channel blocker was used. Sterilized tumor fluids were added to medium of MAT-LyLu cells with the proportion of 20% in vitro. Consequently, it was demonstrated that Dunning rat prostate tumor fluid significantly inhibited proliferation (up to 50%), mitotic index, and labeling index of MAT-LyLu cells (up to 75%) (p<0.05) but stimulated the motility of the cells in vitro.

Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery

Kim, S.J.,Jung, K.H.,Son, M.K.,Park, J.H.,Yan, H.H.,Fang, Z.,Kang, Y.W.,Han, B.,Lim, J.H.,Hong, S.S. Elsevier 2017 Cancer letters Vol.403 No.-

Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization. The PI3K inhibitors, HS-173 and BEZ235 potently suppressed tumor growth and hypoxia, and increased tumor apoptosis in animal models. PI3K inhibitors also induced a regular, flat monolayer of endothelial cells (ECs) in vessels, improving stability of vessel structure, and normalized tumor vessels by increasing vascular maturity, pericyte coverage, basement membrane thickness, and tight-junctions. These effects resulted in a decrease in tumor vessel tortuosity and vessel thinning, and improved vessel function and blood flow. The tumor vessel stabilization effect of the PI3K inhibitor HS-173 also decreased the number of metastatic lung nodules in vivo metastasis model. Furthermore, HS-173 improved the delivery of doxorubicin into the tumor region, enhancing its anticancer effects. Mechanistic studies suggested that PI3K inhibitor HS-173-induced vessel normalization reflected changes in endothelial Notch signaling. Taken together, our findings indicate that vessel normalization by PI3K inhibitors restrained tumor growth and metastasis while improving chemotherapy by enhancing drug delivery into the tumor, suggesting that HS-173 may have a therapeutic value as an enhancer or an anticancer drug.

Extracellular matrix remodeling in vivo for enhancing tumor-targeting efficiency of nanoparticle drug carriers using the pulsed high intensity focused ultrasound

Lee, S.,Han, H.,Koo, H.,Na, J.H.,Yoon, H.Y.,Lee, K.E.,Lee, H.,Kim, H.,Kwon, I.C.,Kim, K. Elsevier Science Publishers 2017 Journal of controlled release Vol.263 No.-

<P>Dense and stiff extracellular matrix (ECM) in heterogeneous tumor tissues can inhibit deep penetration of nanoparticle drug carriers and decreases their therapeutic efficacy. Herein, we suggest the ECM remodeling strategy by the pulsed high intensity focused ultrasound (Pulsed-HIFU) technology for enhanced tumor-targeting of nanoparticles. First, we clearly observed that the tumor-targeting efficacy and tissue penetration of intravenously injected Cy5.5-labled glycol chitosan nanoparticles (Cy5.5-CNPs) were greatly inhibited in tumor tissue containing high collagen and hyaluronan contents in ECM-rich A549 tumor-bearing mice, compared to in ECM-less SCC7. When collagenase or hyaluronidase was treated by intra-tumoral injection, the amount of collagen and hyaluronan decreased in ECM-rich A549 tumor tissues and more Cy5.5-CNPs penetrated inside the tumor tissue, confirmed using non-invasive optical imaging. Finally, in order to break down the stiff ECM structure, ECM-rich A549 tumor tissues were treated with the relatively low power of Pulse-HIFU (20W/cm(2)), wherein acute tissue damage was not observed. As we expected, the A549 tumor tissues showed the remodeling of ECM structure after non-invasive Pulsed-HIFU exposure, which resulted in the increased blood flow, decreased collagen contents, and enhanced penetration of CNPS. Importantly, the tumor targeting efficiency in Pulsed-HIFU-treated A549 tumor tissues was 2.5 times higher than that of untreated tumor tissues. These overall results demonstrate that ECM remodeling and disruption of collagen structure by Pulse-HIFU is promising strategy to enhance the deep penetration and enhanced tumor targeting of nanoparticles in ECM-rich tumor tissues. (C) 2017 Elsevier B.V. All rights reserved.</P>

난소의 상피성 종양에서 신생혈관형성과 Cathepsin D 발현의 상관관계

박일수,배용철 대한부인종양 콜포스코피학회 2003 Journal of Gynecologic Oncology Vol.14 No.3

목적 : 악성종양의 진행과 전이과정에 관여하는 인자로 신생혈관형성 및 단백분해효소에 대한 관심이 높아지고 있으나, 이러한 인자들의 예후에 대한 중요성은 아직 확립되어 있지 않다. 본 연구에서는 양성, 경계성, 악성종양에서 신생혈관형성 유발인자인 VEGF의 발현도와 신생혈관수 및 Cathepsin D의 발현도와의 관계를 알아보고자 한다. 연구 방법 : 1997년부터 1999년까지 경북대학교병원에서 수술로 절제된 난소조직중 장액성 종양 41예와 점액성 종양 50예를 대상으로 면역조직화학적 염색을 이용하여 VEGF와 Cathepsin D의 발현 정도를 분석하였고, CD31에 대한 monoclonal antibody를 이용하여 미세혈관 수를 정량화 하였다. 장액성 종양은 양성 19예, 경계성 3예, 악성 19예였고, 점액성 종양은 양성 2예, 경계성 16예, 악성 14예였다. 결과 : 미세혈관 수, VEGF, Cathepsin D는 점액성과 장액성 모두에서 양성이나 경계성보다 악성에서 현저히 증가하였고, 특히 미세혈관 수는 재발한 1예와 사망한 1예에서 평균보다 높은 수치를 보였다. 그러나 임상인자인 병기, 종양크기 및 환자의 연령과는 통계학적 유의성이 없었다. VEGF 발현과 미세혈관 수 사이에는 유의한 상관 관계가 없으나, Cathepsin D와 VEGF, 신생혈관 수의 발현에는 유의한 상관관계가 있었다. 이는 종양의 혈관형성 에 있어 VEGF 이외에 다른 여러 가지 혈관형성인자 및 성장인자가 관여한다는 것을 보여준다. 결론 : 결론적으로 미세혈관 수, VEGF, 그리고 Cathepsin D의 발현은 난소종양 진행의 유용한 지표로서 여겨지나, 아직 예후에 대한 유의성이 확립되어 있지 않고, 추적기간이 짧아 앞으로 환자의 장기 생존률에 대한 지속적인 연구가 필요할 것으로 사료된다. Objective : Tumor angiogenesis and proteolysis have a role in tumor invasion and metastasis in various types of tumor. But the prognostic significance in ovarian epithelial tumors has not been established. In this study, we evaluate correlation of MVC, VEGF and Cathepsin D expression with progression in ovarian tumor. Methods : Formalin fixed tumor tissues from 41 cases of serous and 50 cases of mucinous tumors were analyzed for the expresssion of VEGF and Cathepsin D by immunohistochemical stain. The authors quantified microvessel counts (MVC) using monoclonal antibody for CD31. The serous tumors included 19 cases of benign, 3 cases of borderline and 19 cases of malignant tumors. The mucinous tumors included 20 cases of benign, 16 cases of borderline and 14 cases of malignant tumors. Results : MVC, VEGF and cathepsin D expression in malignant tumors were significantly higher than those in benign or borderline malignancy of both serous and mucinous tumors. One case of recurrence and another one case of death showed highly counted microvessels. But, there was no significant correlation as to FIGO stage, tumor size or patient’s age. There was no correlation between VEGF expression and MVC, however significant correlation was found between expression of Cathepsin D and VEGF and MVC. These results suggest that other angiogenic factors may affect in the regulation of angiogenesis. Conclusion : MVC, VEGF and Cathepsin D expression seems to be suggested as a useful indicator of progression in ovarian tumors. But, the prognostic significance cannot be fully established and additionally long-term follow up study for patient’s survival rate is needed.

고관절주위 종양에 대한 임상적 고찰

김성준 ( Sung Joon Kim ),최일용 ( Il Yong Choi ),김태승 ( Tai Seung Kim ),안성철 ( Sung Chul Ahn ) 대한고관절학회 1991 Hip and Pelvis Vol.3 No.1

From January 1983 to December 1990, Sixty-six patients who have tumors around the hip joint and were confirmed their diagnosis by histopathological study have been reviewed and the following results were obtained. 1. There were forty-three cases(65.2%) of benign tumor and twenty-three(34.8%) malignant tumor. 2. Of the sixty-six patient, thirty-four were male and thirty-two female. In benign tumor, they shows relatively even distribution in age but in malignant tumors, thirteen cases(56.5%) were in the 5th and 6th decade. 3. Among the benign tumors, the soft tissue origin was nineteen cases and bony origin twenty-four. The most common tumor in soft tissue origin was lipoma (six cases(31.6%)) and bony origin unicameral bone cyst (nine cases(37.5%)). In malig- nent tumors. the metastatic carcinoma was most common (twelve cases(52.5%)) and the liver was most common primary site of cancer. 4. The most common chief complaint was mass (fourteen cases(32.6%)) in benign tumor and painful mass (eight(34.8%)) in malignant tumor. The duration of symptom ranged from 1 day to 33 years with an average of 3.6 years in benign tumor and from 2 weeks to 5 years (average 6 months) in malignant tumor. 5. Most of the benign tumors were treated by local excision, and malignant tumors were treated by wide excision, chemotherapy, radiation therapy, bipolar hemiarthroplasty, and tumor prosthesis or combination of them.

Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment

Park, Jin-Sung,Kim, Il-Kug,Han, Sangyeul,Park, Intae,Kim, Chan,Bae, Jeomil,Oh, Seung Ja,Lee, Seungjoo,Kim, Jeong Hoon,Woo, Dong-Cheol,He, Yulong,Augustin, Hellmut G.,Kim, Injune,Lee, Doheon,Koh, Gou Y Cell Press 2016 CANCER CELL Vol. No.

<P><B>Summary</B></P> <P>A destabilized tumor vasculature leads to limited drug delivery, hypoxia, detrimental tumor microenvironment, and even metastasis. We performed a side-by-side comparison of ABTAA (Ang2-Binding and Tie2-Activating Antibody) and ABA (Ang2-Blocking Antibody) in mice with orthotopically implanted glioma, with subcutaneously implanted Lewis lung carcinoma, and with spontaneous mammary cancer. We found that Tie2 activation induced tumor vascular normalization, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened lactate acidosis, and reduced tumor growth and metastasis. Moreover, ABTAA favorably altered the immune cell profile within tumors. Together, our findings establish that simultaneous Tie2 activation and Ang2 inhibition form a powerful therapeutic strategy to elicit a favorable tumor microenvironment and enhanced delivery of a chemotherapeutic agent into tumors.</P> <P><B>Highlights</B></P> <P> <UL> <LI> ABTAA-induced Tie2 activation and Ang2 inhibition normalize tumor vasculature </LI> <LI> Tumor vessel normalization leads to enhanced blood perfusion and drug delivery </LI> <LI> Tumor vessel normalization lessens hypoxia, acidosis, tumor growth, and metastasis </LI> <LI> Tie2 activation favorably alters the tumor microenvironment and immune infiltration </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Surgery of the Tumors in the Ventricular System

Hong, Sang-Won,Choi, Ha-Young,Koh, Eun-Jeong The Korean Neurosurgical Society 2006 Journal of Korean neurosurgical society Vol.39 No.1

Objective : The authors study on the clinical presentations and the surgical outcomes of the tumors in the ventricular system. Methods : 15 patients with ventricular tumor were studied. The clinical presentation, radiological findings, different surgical approaches, and outcome were analyzed. Tumors were classified into three groups based on their locations in MRI : lateral, third and fourth ventricle. Surgical methods were transcortical approach in eight patients, transcallosal approach in four, median suboccipital approach in two, and subfrontal approach in one. Gross total removal was achieved in 10 patients. Subtotal resections were performed in the rest. Glasgow outcome scale was used for evaluation of the surgical outcome. Results : Main clinical presentations were chronic headache in patients with the tumor in the lateral ventricular tumor and sudden onset of headache and consciousness change in patients with the tumor in the third and fourth ventricular tumor Development of hydrocephalus was more predominant in patients with the tumors in the third ventricle. Postoperatively, good outcome [Glasgow outcome scale IV, V] were in 73%, and better results was observed in patients with the tumors in the lateral ventricular tumor. The differences of outcome according to surgical approach were not recognized, even though it was not reliable statistically. Conclusion : In ventricular tumor, postoperative outcome is not good in patients with sudden development of headache, hydrocephalus, high grade tumor. Outcome is good in patients with the tumor in the lateral ventricle relatively. There is no difference in outcome according to the approach method to the tumors. And it is necessary to be aware of various approach methods to the tumors and anatomy surrounding the ventricle for avoidance of neurological complications.

Homologous tumor cell membrane vesicles active preferential self‑recognition of tumor cells in vitro

Wu Chenghu,Yu Ailin,Chen Yue,Fan Mingbo 한국응용생명화학회 2022 Applied Biological Chemistry (Appl Biol Chem) Vol.65 No.1

Cell membrane vesicles, as delivery carriers of drugs or biological agents in vivo, are an important therapeutic mode in the study of disease treatment. Tumor membrane-derived vesicles have been widely used in tumor therapy because of their good tumor enrichment effect. The most common method is the surface of nanoparticles coated with tumor cell membrane, which can effectively prolong the circulation time of particles in the blood and the enrichment of tumors. In this study, we prepared vesicles of different tumor cell membrane derivate and studied their targeting to tumors detailly. The results showed that homologous vesicles have high targeting to homologous tumor cells. The fluorescence of vesicles in homologous tumor cells was significantly higher than that in other tumor cells. This study will provide a new strategy and guidance for the clinical treatment of cancer based on the tumor cell membrane system.

Effect of Tumor Hypoxia on Efficacy of Tirapazamine Combined with Fractonated Irradiation in Mouse Tumor

김일한(Il Han Kim) 대한방사선종양학회 2000 Radiation Oncology Journal Vol.18 No.2

목 적 : 종양내 저산소상태는 저산소세포치사제에 의하여 극복이 가능하다. 방사선의 반응을 증강시키는 tirapazamine 의 효과가 마우스 종양에서 분할방사선조사와 병용된 상태에서 종양내 산소상태에 따라 어떠한 영향을 받는가를 확인하고자 하였다. 대상 및 방법 : 대조군 및 저산소 상태의 종양을 수립하기 위하여 정상 및 4주전에 방사선 조사를 받았던 마우스의 등과 하지에 RIF- 1 종양을 이식하였다. 종양이 일정한 크기에 도달하면, 대조군 및 저산소 상태 종양에 대하여 생리식염수(0.02 mlg), tirapazamine (0.08 mM/kg), 방사선조사(2.5 Gy), tirapazamine 과 방사선조사의 병용 등을 사용하여 4일간 8회의 과분할 치료를 시행하였다. 등의 종양 체적이 4 배로 증가하거나 하지의 종양 단면이 2배로 증가할때 까지 종양의 크기 변화를 측정하여 얻은 종양성장의 지연을 기준으로 각 치료에 대한 반응을 평가하였다. 결 과 : 등 및 하지의 정상 및 저산소종양의 평균증식양상으로 부터 tirapazamine이 방사선의 반응을 증강시켰음을 알 수 있다. tirapazamine에 의한 방사선증강효과는 초기의 종양체적 또는 종양단면적을 기준으로 한 증식지연실험 결과 등의 정상종양에서는 1.9배, 저산소종양에서는 2.4배였으며 하지의 정상종양에서는 1.85배, 저산소종양에서는 1.6배였다. 초기종양체적의 4배 증식 또는 종양단면적의 2배 증식까지의 기간을 기준으로 설정한 증식지연실험결과 등의 정상종양에서는 1.48배, 저산소종양에서는 2.02배였으며 하지의 정상종양에서는 1.85배, 저산소종양에서는 1.6배였다. 결 론 : 분할 방사선조사에 tirapazamine을 병용할 경우 방사선조사효과는 증강되며, 저산소상태에 있는 마우스 종양에서의 증강효과가 대조 종양에서의 증강효과와 동일하거나 더욱 양호할 가능성을 제시할 수 있었다. Purpose :Tumor hypoxia can be overcome with hypoxic cytotoxin. In mouse tumor, tirapazamine's efficacy of the potentiating radiation effect was tested by the tumor oxygenation status combined with hyperfactionated radiotherapy. Materials and Methods :The control and hypoxic mouse tumors were established by inoculation of RIF- 1 tumor cells into the normal or previously irradiated back and thigh of C3H mice. When the tumors reached a proper size, both the control and hypoxic tumors were given hyperfractionated treatments (8 fractions/4 days) with saline (0.02 ml/g), tirapazamin (0.08 mM/0.02 ml/kg), irradiation (2.5 Gy), irradiation combined with tirapazamine given 30 minutes prior to each irradiation. The response was evaluated by the growth delay assay by measuring tumor size from day 0 (12 hrs prior to the first fractionation) to the day when the volume had 4- fold increase or cross sectional area had 2- fold increase. Results :Overall growth pattern showed that tirapazamine potentiated radiation effect in back and thigh tumors grew in the normal and preirradiated tumor bed. With growth delay assay using reference point of initial tumor volume or cross sectional area, tirapazamine potentiated radiation effect 1.9 times for the control and 2.4 times for the hypoxic tumors in back, and 1.85 times for the control and 1.6 times for the hypoxic tumors. With reference of 4- fold increase of the initial volume or 2- fold increase of the cross sectional area, tirapazamine potentiated radiation effect 1.48 times for the control and 2.02 times for the hypxic tumors in back, and 1.85 times for the control and 1.6 times for the hypoxic tumors. Conclusion : Present result indicated that radiation response of hypoxic tumors was potentiated by tirapazamine in the back or thigh tumors grew in the control or preirradiated tumor bed, and potentiation of the hypoxic tumors was equal to or greater than that of the control tumors in the back or thigh.