Plateau hypoxia improves tumor immune microenvironment and inhibits subcutaneous tumor growth of colorectal cancer

ZHAO Sijie; WANG Meng; GAO Yuan; YANG Fang; HU Shaofan; MIAO Hongming

doi:10.16016/j.2097-0927.202410011

您当前的位置：

首页 >

文章列表页 >

Plateau hypoxia improves tumor immune microenvironment and inhibits subcutaneous tumor growth of colorectal cancer

Monographic Reports | 更新时间：2025-01-10

- Plateau hypoxia improves tumor immune microenvironment and inhibits subcutaneous tumor growth of colorectal cancer
- Journal of Army Medical University Vol. 47, Issue 1, Pages: 38-50(2025)
- 作者机构：
  
  陆军军医大学（第三军医大学）高原军事医学系病理生理学教研室，极端环境医学教育部重点实验室，重庆
- 作者简介：
  
  MIAO Hongming， E-mail： hongmingmiao@sina.com
- 基金信息：
  
  Supported by the Postdoctoral Science Fund of Chongqing(CSTB2023NSCQ-BHX0221);the Special Project for Young Scholars of Science and Technology Innovation Capacity Promotion of Army Medical University(2023XQN25)
- DOI：10.16016/j.2097-0927.202410011
  CLC：
- Published：15 January 2025，
  
  Received：08 October 2024，
  
  Revised：06 December 2024，
- 稿件说明：
移动端阅览
赵思洁,王猛,高源,等.高原低氧改善肿瘤免疫微环境并抑制结直肠癌皮下肿瘤生长[J].陆军军医大学学报,2025,47(01):38-50.

ZHAO Sijie,WANG Meng,GAO Yuan,et al.Plateau hypoxia improves tumor immune microenvironment and inhibits subcutaneous tumor growth of colorectal cancer[J].J Army Med Univ,2025,47(1):38-50.
赵思洁,王猛,高源,等.高原低氧改善肿瘤免疫微环境并抑制结直肠癌皮下肿瘤生长[J].陆军军医大学学报,2025,47(01):38-50. DOI：10.16016/j.2097-0927.202410011.

ZHAO Sijie,WANG Meng,GAO Yuan,et al.Plateau hypoxia improves tumor immune microenvironment and inhibits subcutaneous tumor growth of colorectal cancer[J].J Army Med Univ,2025,47(1):38-50. DOI：10.16016/j.2097-0927.202410011.

摘要

目的

探究高原低氧环境对结直肠癌体内生长及肿瘤微环境的影响。

方法

采用随机数字表法将雄性6周龄BALB/C与C57BL/6小鼠（体质量18~20 g）各自分为2组，分别置于低压氧仓（10%氧气，海拔约5 600 m，高原低氧组）和SPF级动物实验中心（21%O

，海拔约300 m，平原常氧组）饲养，C57BL/6小鼠每组8只，BALB/C小鼠每组7只。对C57BL/6小鼠皮下接种MC38、对BALB/C小鼠皮下接种CT26以构建结直肠癌皮下肿瘤模型。观察C57BL/6与BALB/C小鼠肿瘤大小并统计肿瘤质量。收集C57BL/6小鼠的肿瘤、外周血以及脾脏中的免疫细胞，流式细胞术对巨噬细胞、T淋巴细胞、IFN-γ

T淋巴细胞以及髓源性抑制细胞（myeloid-derived suppressor cells，MDSC）进行检测，分析这些免疫细胞在平原常氧和高原低氧环境下的变化情况。

结果

与平原常氧组C57BL/6与BALB/C小鼠相比，高原低氧组2种小鼠皮下肿瘤生长都被显著抑制（0.17

0.09 g，1.38

0.51 g，

0.01）与平原常氧组C57BL/6小鼠相比，高原低氧组C57BL/6小鼠肿瘤微环境中的M2巨噬细胞比例显著降低（22.13%

15.90%，

0.05）；MDSC比例减少（2.06%

1.05%，

0.01），其中单核性MDSC（M-MDSC：Ly6C

）亚群比例显著降低（60.97%

41.13%，

0.01），而粒性MDSC（PMN-MDSC：Ly6G

）比例无显著差异（10.97%

9.70%，

0.05）；CD8

T细胞比例显著升高（41.25%

51.18%，

0.01），CD4

T细胞比例降低（48.70%

41.93%，

0.05）；IFN-γ

T、IFN-γ

CD4

T、IFN-γ

CD8

T细胞比例均显著增高（28.58%

59.65%，23.33%

53.65%，36.9%

66.48%，

0.01）；外周血中CD4

T淋巴细胞和M1巨噬细胞比例都降低（84.98%

78.43%，5.86%

4.01%，

0.01），MDSC及PMN-MDSC（Ly6G

）比例增高（4.47%

16.43%，36.56%

62.97%，

0.01）；脾脏中CD8

T淋巴细胞比例和IFN-γ

CD8

T淋巴细胞比例都显著降低（33.05%

27.68%，5.13%

1.58%，

0.01）。

结论

高原低氧可以增强肿瘤微环境内免疫应答并抑制结直肠癌皮下肿瘤的生长，但却抑制全身性免疫应答。

Abstract

Objective To investigate the effects of plateau hypoxia on the growth and tumor microenvironment of colorectal carcinoma

in vivo

.Methods‍　‍A total of 16 male BALB/C mice （6 weeks old， weight 18-20 g） were randomly divided into plateau hypoxic group and plain normoxic group， with 8 mice in each group， while 14 male C57BL/6 mice were grouped in same way， with 7 mice in each group. The mice in the plateau hypoxic group were housed in a low-pressure oxygen （10%） chamber to simulate an altitude of approximately 5 600 m， while the mice of the other group was maintained in SPF-grade normal atmospheric conditions （21% oxygen， at an altitude of about 300 m）. Colorectal tumor MC38 cells and colon adenocarcinoma CT26 cells were subcutaneously implanted into C57BL/6 mice and BALB/C mice， respectively to construct subcutaneous tumor-bearing mouse models. Then the tumor size and weight were measured in 4 groups of mice. After the tumor tissues， spleen and blood samples were collected in the C57BL/6 mice. Flow cytometry was used to determine the percentages of macrophages，

T lymphocytes， IFN-γ

T lymphocytes， and myeloid-derived suppressor cells （MDSC）. The differences in these immune cells were compared between the cells from the plateau hypoxic group and those from the plain normoxic group. Results‍　‍The weight of subcutaneous tumor mass was significantly inhibited in both C57BL/6 and BALB/C mice from the plateau hypoxic group than those from the 2 plain normoxic groups （0.17

0.09 g， 1.38

0.51 g，

0.01）. When compared with the immune cells from the tumor mass of the plain normoxic C57BL/6 mice， the percentage of M2-type macrophages was reduced in the tumor tissue from the plateau hypoxic mice（22.13%

15.90%，

0.05）， so was that of MDSC （2.06%

1.05%，

0.01）， particularly in the monocytic （M）-MDSC subgroup （60.97%

41.13%，

0.01）. While， no significant change was observed in the proportion of the polymorphonuclear （PMN）-MDSC subgroup （10.97%

9.70%，

0.05）. Additionally， the percentage of CD4

T cells was significantly reduced （48.70%

41.93%，

0.05）， whereas that of CD8

T cells was obviously increased （41.25%

51.18%，

0.05）， along with a notable rise in the proportions of IFN-γ

T， IFN-γ

CD4

T and IFN-γ

CD8

T cells （28.58%

59.65%， 23.33%

53.65%， 36.9%

66.48%，

0.01）. However， between the peripheral blood samples of the 2 groups of C57BL/6 mice， the proportions of M1-type macrophages and CD4

T cells were reduced （84.98%

78.43%， 5.86%

4.01%，

0.01）， and those of MDSC and PMN-MDC were increased （4.47%

16.43%， 36.56%

62.97%，

0.01）. In the spleen tissues， notable decreases were observed in the proportions of CD8

T cells and IFN-γ

CD8

T cells between the 2 groups （33.05%

27.68%， 5.13%

1.58%，

0.01）. Conclusion Plateau hypoxia improves the immune response within the tumor microenvironment， and inhibits subcutaneous tumor growth of colorectal cancer， but suppresses systemic immune response.

关键词

高原低氧肿瘤微环境结直肠癌免疫应答

Keywords

plateauhypoxiatumor microenvironmentcolorectal cancerimmune response

references

BRAY F， LAVERSANNE M， SUNG H， et al. Global cancer statistics 2022： GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］. CA Cancer J Clin， 2024， 74（3）： 229-263. DOI： 10.3322/caac.21834http://dx.doi.org/10.3322/caac.21834.

HOSSAIN M S， KARUNIAWATI H， JAIROUN A A， et al. Colorectal cancer： a review of carcinogenesis， global epidemiology， current challenges， risk factors， preventive and treatment strategies［J］. Cancers， 2022， 14（7）： 1732. DOI： 10.3390/cancers14071732http://dx.doi.org/10.3390/cancers14071732.

BRITO J， SIQUES P， PENA E. Long-term chronic intermittent hypoxia： a particular form of chronic high-altitude pulmonary hypertension［J］. Pulm Circ， 2020， 10（1 Suppl）： 5-12. DOI： 10.1177/2045894020934625http://dx.doi.org/10.1177/2045894020934625.

HOU Y， WANG X B， ZHANG Y， et al. Highland mate： Edible and functional foods in traditional medicine for the prevention and treatment of hypoxia-related symptoms［J］. Curr Opin Pharmacol， 2021， 60： 306-314. DOI： 10.1016/j.coph.2021.07.018http://dx.doi.org/10.1016/j.coph.2021.07.018.

RICHALET J P， HERMAND E， LHUISSIER F J. Cardiovascular physiology and pathophysiology at high altitude［J］. Nat Rev Cardiol， 2024， 21（2）： 75-88. DOI： 10.1038/s41569-023-00924-9http://dx.doi.org/10.1038/s41569-023-00924-9.

ZHOU J M， HE R F， SHEN Z Z， et al. Altitude and metabolic syndrome in China： beneficial effects of healthy diet and physical activity［J］. J Glob Health， 2023， 13： 04061. DOI： 10.7189/jogh.13.04061http://dx.doi.org/10.7189/jogh.13.04061.

CALDERÓN-GERSTEIN W S， TORRES-SAMANIEGO G. High altitude and cancer： an old controversy［J］. Respir Physiol Neurobiol， 2021， 289： 103655. DOI： 10.1016/j.resp.2021.103655http://dx.doi.org/10.1016/j.resp.2021.103655.

BURTSCHER J，MILLET G P，RENNER-SATTLER K， et al. Moderate altitude residence reduces male colorectal and female breast cancer mortality more than incidence： therapeutic implications？［J］. Cancers， 2021， 13（17）： 4420. DOI： 10.3390/cancers13174420http://dx.doi.org/10.3390/cancers13174420.

ZHOU M G， WANG H D， ZHU J， et al. Cause-specific mortality for 240 causes in China during 1990-2013： a systematic subnational analysis for the global burden of disease study 2013［J］. Lancet， 2016， 387（10015）： 251-272. DOI： 10.1016/S0140-6736（15）00551-6http://dx.doi.org/10.1016/S0140-6736（15）00551-6.

GARRIDO D I， GARRIDO S M. Cancer risk associated with living at high altitude in Ecuadorian population from 2005 to 2014［J］. Clujul Med， 2018， 91（2）： 188-196. DOI： 10.15386/cjmed-932http://dx.doi.org/10.15386/cjmed-932.

汪腾，高源，赵昆，等. 小鼠THBS1基因敲除改善内脏脂肪免疫微环境并抑制结直肠癌腹腔种植转移［J］. 陆军军医大学学报， 2023， 45（18）： 1907-1915. DOI： 10.16016/j.2097-0927.202303119http://dx.doi.org/10.16016/j.2097-0927.202303119.

WANG T， GAO Y， ZHAO K， et al. Knockout of THBS1 gene improves immune microenvironment of visceral fat and inhibits intraperitoneal implantation and metastasis of colorectal cancer in mice［J］. J Army Med Univ， 2023， 45（18）： 1907-1915. DOI： 10.16016/j.2097-0927.202303119http://dx.doi.org/10.16016/j.2097-0927.202303119.

SUNG H J， MA W Z， STAROST M F， et al. Ambient oxygen promotes tumorigenesis［J］. PLoS One， 2011， 6（5）： e19785. DOI： 10.1371/journal.pone.0019785http://dx.doi.org/10.1371/journal.pone.0019785.

BAI J， LI L J， LI Y H， et al. Genetic and immune changes in Tibetan high-altitude populations contribute to biological adaptation to hypoxia［J］. Environ Health Prev Med， 2022， 27： 39. DOI： 10.1265/ehpm.22-00040http://dx.doi.org/10.1265/ehpm.22-00040.

SINGLETON D C， MACANN A， WILSON W R. Therapeutic targeting of the hypoxic tumour microenvironment［J］. Nat Rev Clin Oncol， 2021， 18（12）： 751-772. DOI： 10.1038/s41571-021-00539-4http://dx.doi.org/10.1038/s41571-021-00539-4.

WU Q H， YOU L， NEPOVIMOVA E， et al. Hypoxia-inducible factors： master regulators of hypoxic tumor immune escape［J］. J Hematol Oncol， 2022， 15（1）： 77. DOI： 10.1186/s13045-022-01292-6http://dx.doi.org/10.1186/s13045-022-01292-6.

HIAM-GALVEZ K J， ALLEN B M， SPITZER M H. Systemic immunity in cancer［J］. Nat Rev Cancer， 2021， 21（6）： 345-359. DOI： 10.1038/s41568-021-00347-zhttp://dx.doi.org/10.1038/s41568-021-00347-z.

THIERSCH M， SWENSON E R， HAIDER T， et al. Reduced cancer mortality at high altitude： the role of glucose， lipids， iron and physical activity［J］. Exp Cell Res， 2017， 356（2）： 209-216. DOI： 10.1016/j.yexcr. 2017.03.048http://dx.doi.org/10.1016/j.yexcr.2017.03.048.

MEEHAN R T. Immune suppression at high altitude［J］. Ann Emerg Med， 1987， 16（9）： 974-979. DOI： 10.1016/s0196-0644（87）80743-6http://dx.doi.org/10.1016/s0196-0644（87）80743-6.

陈海威，张津津，李良，等. 不同习服方法对军人急进高原急性高原反应的干预效果比较［J］. 解放军医药杂志， 2018， 30（4）： 104-106. DOI： 10.3969/j.issn.2095-140X.2018.04.027http://dx.doi.org/10.3969/j.issn.2095-140X.2018.04.027.

CHEN H W， ZHANG J J， LI L， et al. Effect comparison of different acclimatization methods in intervention of acute mountain sickness in military personnel during rapidly entering plateau［J］. Med Pharm J Chin PLA， 2018， 30（4）： 104-106. DOI： 10.3969/j.issn.2095-140X.2018.04.027http://dx.doi.org/10.3969/j.issn.2095-140X.2018.04.027.

许琴，王瑜，沈才福，等.低压氧诊疗疾病的现状与研究进展［J］.新疆医学，2020，50（02）：118-120，123.

XU Q， WANG Y， SHEN C F， et al. Present situation and research progress of low pressure oxygen in diagnosis and treatment of diseases［J］. Xinjiang Med J， 2020， 50（2）：118-120，123.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

APE1 mediates the occurrence and development of colitis-associated colorectal cancer through immunosuppressive tumor microenvironment

Role and mechanism of ACSS2-mediated epithelial-mesenchymal transition in ethanol-promoted migration of colorectal cancer

Knockout of THBS1 gene improves immune microenvironment of visceral fat and inhibits intraperitoneal implantation and metastasis of colorectal cancer in mice

Effects of PRKCH on CD8+T cell function and melanoma immunotherapy

Comparison of 2 different mouse models of colorectal cancer and their application

Related Author

CHEN Tianyi

LI Chaofan

BAO Lingbo

CHEN Qian

HU Nana

YANG Yuxin

ZHANG Lei

WANG Dong

Related Institution

Cancer Center, Army Medical Center of PLA

Yu-Yue Pathology Scientific Research Center

Jinfeng Laboratory

Department of Environmental Health, Faculty of Military Preventive Medicine, Army Medical University (Third Military Medical University)

School of Public Health, Guizhou Medical University

⁰