Current research status of Tibetan lung cancers_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANG Xin ¹ ,  CHE Guowei ²

1. Department of Thoracic Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, P.R.China;
2. Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R.China;

Corresponding author：

CHE Guowei, Email: cheguowei_hx@aliyun.com

Keywords：

Lung cancer; Tibetan population; Tibet

DOI：

10.7507/1007-4848.201811048

Video：

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Tibetan population has been living in Tibet plateau for more than thousands of years ago. Although, the environment is unlikely to be an ideal place for residence. They have evolved genetical and physiological adaptions living in Tibetan highlands. In recent several years, foreign scientists have noticed that lung cancer mortality is reduced at high altitude. Many in vitro and in vivo experiments explored the mechanism of this phenomenon. In this review we discuss the lung cancer incidence and mortally of Tibetan population, as well as the possible underlying mechanism including oxygen level, radiation, inhalable particulate matter, metabolism, hypoxic induced factor pathway and immune system. But, the clinical data as well as basic researches of Tibetan population remain insufficient, which required further investigation.

Citation： WANG Xin, CHE Guowei. Current research status of Tibetan lung cancers. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2019, 26(9): 920-925. doi: 10.7507/1007-4848.201811048 Copy

1.	Simeonov KP, Himmelstein DS. Lung cancer incidence decreases with elevation: evidence for oxygen as an inhaled carcinogen. Peer J, 2015, 3: e705.
2.	Youk AO, Buchanich JM, Fryzek J, et al. An ecological study of cancer mortality rates in high altitude counties of the United States. High Alt Med Biol, 2012, 13(2): 98-104.
3.	Van Pelt WR. Epidemiological associations among lung cancer, radon exposure and elevation above sea level--a reassessment of Cohen’s county level radon study. Health Physics, 2003, 85(4): 397-403.
4.	Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC cancer, 2006, 6: 264.
5.	Aceituno-Madera P, Buendia-Eisman A, Olmo FJ, et al. Melanoma, altitude, and UV-B radiation. Actas Dermosifiliogr, 2011, 102(3): 199-205.
6.	陈万青, 孙可欣, 郑荣寿, 等. 2014 年中国分地区恶性肿瘤发病和死亡分析. 中国肿瘤, 2018, 27(1): 1-14.
7.	于跃, 扎西宗吉, 白国霞. 西藏 2014~2015 年恶性肿瘤发病和死亡性别差异分析. 中华疾病控制杂志, 2017, 21(1): 105-106.
8.	Mori-Chavez P, Upton AC, Salazar M, et al. Influence of altitude on late effects of radiation in RF-Un mice: observations on survival time, blood changes, body weight, and incidence of neoplasms. Cancer Res, 1970, 30(4): 913-928.
9.	Mori-Chavez P, Upton AC, Salazar M, et al. Influence of transitory, as compared with permanent, high-altitude exposure on the pathogenesis of spontaneous and X-ray-induced neoplasms in RF-Un mice. Cancer Res, 1974, 34(2): 328-336.
10.	Sung HJ, Ma W, Starost MF, et al. Ambient oxygen promotes tumorigenesis. PloS One, 2011, 6(5): e19785.
11.	Jefferson JA, Simoni J, Escudero E, et al. Increased oxidative stress following acute and chronic high altitude exposure. High Alt Med Biol, 2004, 5(1): 61-69.
12.	Aldashev AA, Kojonazarov BK, Amatov TA, et al. Phosphodiesterase type 5 and high altitude pulmonary hypertension. Thorax, 2005, 60(8): 683-687.
13.	Gasche C, Chang CL, Rhees J, et al. Oxidative stress increases frame shift mutations in human colorectal cancer cells. Cancer Res, 2001, 61(20): 7444-7448.
14.	Askew EW. Work at high altitude and oxidative stress: antioxidant nutrients. Toxicology, 2002, 180(2): 107-119.
15.	Wu T, Kayser B. High altitude adaptation in Tibetans. High Alt Med Biol, 2006, 7(3): 193-208.
16.	Beall CM. Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci USA, 2007, 104(Suppl 1): 8655-8660.
17.	Chen QH, Ge RL, Wang XZ, et al. Exercise performance of Tibetan and Han adolescents at altitudes of 3,417 and 4,300 m. J Appl Physiol, (1985), 1997, 83(2): 661-667.
18.	Beall CM. Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. Integr Comp Biol, 2006, 46(1): 18-24.
19.	Beall CM. Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum Biol, 2000, 72(1): 201-228.
20.	陈万青, 邹小农, 李连弟, 等. 西藏自治区恶性肿瘤流行特征. 中国肿瘤, 2005, (6): 364-366.
21.	黎卫平, 陈超, 臧宝彩, 等. 西藏自治区拉萨市 2727 例恶性肿瘤发生顺位分析. 西藏大学学报 (自然科学版), 2011, 26(1): 52-55.
22.	德庆旺姆. 西藏地区藏族人群肺癌临床分析. 西藏科技, 2013, (11): 39-40.
23.	Hayes DP. Cancer protection related to solar ultraviolet radiation, altitude and vitamin D. Med Hypotheses, 2010, 75(4): 378-382.
24.	Bikle DD. Extraskeletal actions of vitamin D. Ann N Y Acad Sci, 2016, 1376(1): 29-52.
25.	Hamra GB, Guha N, Cohen A, et al. Outdoor particulate matter exposure and lung cancer: a systematic review and meta-analysis. Environ Health Perspect, 2014, 122(9): 906-911.
26.	Moen I, Stuhr LE. Hyperbaric oxygen therapy and cancer--a review. Target Oncol, 2012, 7(4): 233-242.
27.	Hatfield SM, Kjaergaard J, Lukashev D, et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Trans Med, 2015, 7(277): 277ra230.
28.	Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer, 2014, 14(11): 709-721.
29.	Murray AJ, Horscroft JA. Mitochondrial function at extreme high altitude. J Physiol, 2016, 594(5): 1137-1149.
30.	Semenza GL, Nejfelt MK, Chi SM, et al. Hypoxia-inducible nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene. Proc Natl Acad Sci USA, 1991, 88(13): 5680-5684.
31.	Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol, 1992, 12(12): 5447-5454.
32.	Ema M, Taya S, Yokotani N, et al. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA, 1997, 94(9): 4273-4278.
33.	Brown JM. Tumor hypoxia in cancer therapy. Methods Enzymol, 2007, 435: 297-321.
34.	Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev, 2007, 26(2): 225-239.
35.	Zhao J, Du F, Shen G, et al. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis, 2015, 6: e1600.
36.	Liu ZJ, Semenza GL, Zhang HF. Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B, 2015, 16(1): 32-43.
37.	Manalo DJ, Rowan A, Lavoie T, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood, 2005, 105(2): 659-669.
38.	Wong CC, Zhang H, Gilkes DM, et al. Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J Mol Med (Berlin, Germany), 2012, 90(7): 803-815.
39.	Lanikova L, Reading NS, Hu H, et al. Evolutionary selected Tibetan variants of HIF pathway and risk of lung cancer. Oncotarget, 2017, 8(7): 11739-11747.
40.	Woolcott OO, Castillo OA, Gutierrez C, et al. Inverse association between diabetes and altitude: a cross-sectional study in the adult population of the United States. Obesity (Silver Spring), 2014, 22(9): 2080-2090.
41.	Woolcott OO, Gutierrez C, Castillo OA, et al. Inverse association between altitude and obesity: A prevalence study among andean and low-altitude adult individuals of Peru. Obesity (Silver Spring), 2016, 24(4): 929-937.
42.	Duan W, Shen X, Lei J, et al. Hyperglycemia, a neglected factor during cancer progression. Biomed Res Int, 2014, 2014: 461917.
43.	Woolcott OO, Ader M, Bergman RN. Glucose homeostasis during short-term and prolonged exposure to high altitudes. Endocr Rev, 2015, 36(2): 149-173.
44.	Hensley CT, Faubert B, Yuan Q, et al. Metabolic Heterogeneity in Human Lung Tumors. Cell, 2016, 164(4): 681-694.
45.	Labak CM, Wang PY, Arora R, et al. Glucose transport: meeting the metabolic demands of cancer, and applications in glioblastoma treatment. Am J Cancer Res, 2016, 6(8): 1599-1608.
46.	Huang C, Freter C. Lipid metabolism, apoptosis and cancer therapy. Inter J Molecular Sci, 2015, 16(1): 924-949.
47.	Hashmi S, Wang Y, Suman DS, et al. Human cancer: is it linked to dysfunctional lipid metabolism? Biochim Biophys Acta, 2015, 1850(2): 352-364.
48.	Ackerman D, Simon MC. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol, 2014, 24(8): 472-478.
49.	Stock C, Gassner B, Hauck CR, et al. Migration of human melanoma cells depends on extracellular pH and Na⁺/H⁺ exchange. J Physiol, 2005, 567(Pt 1): 225-238.
50.	Ibrahim-Hashim A, Cornnell HH, Abrahams D, et al. Systemic buffers inhibit carcinogenesis in TRAMP mice. J Urol, 2012, 188(2): 624-631.
51.	Azzarito T, Lugini L, Spugnini EP, et al. Effect of modified alkaline supplementation on syngenic melanoma growth in CB57/BL Mice. PloS One, 2016, 11(7): e0159763.
52.	Robey IF, Nesbit LA. Investigating mechanisms of alkalinization for reducing primary breast tumor invasion. Biomed Res Int, 2013, 2013: 485196.
53.	Swenson ER. Hypoxia and its acid-base consequences: from mountains to malignancy. Adv Exp Med Biol, 2016, 903: 301-323.
54.	Wang JS, Wu CK. Systemic hypoxia affects exercise-mediated antitumor cytotoxicity of natural killer cells. J Appl Physiol (1985), 2009, 107(6): 1817-1824.

1. Simeonov KP, Himmelstein DS. Lung cancer incidence decreases with elevation: evidence for oxygen as an inhaled carcinogen. Peer J, 2015, 3: e705.
2. Youk AO, Buchanich JM, Fryzek J, et al. An ecological study of cancer mortality rates in high altitude counties of the United States. High Alt Med Biol, 2012, 13(2): 98-104.
3. Van Pelt WR. Epidemiological associations among lung cancer, radon exposure and elevation above sea level--a reassessment of Cohen’s county level radon study. Health Physics, 2003, 85(4): 397-403.
4. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC cancer, 2006, 6: 264.
5. Aceituno-Madera P, Buendia-Eisman A, Olmo FJ, et al. Melanoma, altitude, and UV-B radiation. Actas Dermosifiliogr, 2011, 102(3): 199-205.
6. 陈万青, 孙可欣, 郑荣寿, 等. 2014 年中国分地区恶性肿瘤发病和死亡分析. 中国肿瘤, 2018, 27(1): 1-14.
7. 于跃, 扎西宗吉, 白国霞. 西藏 2014~2015 年恶性肿瘤发病和死亡性别差异分析. 中华疾病控制杂志, 2017, 21(1): 105-106.
8. Mori-Chavez P, Upton AC, Salazar M, et al. Influence of altitude on late effects of radiation in RF-Un mice: observations on survival time, blood changes, body weight, and incidence of neoplasms. Cancer Res, 1970, 30(4): 913-928.
9. Mori-Chavez P, Upton AC, Salazar M, et al. Influence of transitory, as compared with permanent, high-altitude exposure on the pathogenesis of spontaneous and X-ray-induced neoplasms in RF-Un mice. Cancer Res, 1974, 34(2): 328-336.
10. Sung HJ, Ma W, Starost MF, et al. Ambient oxygen promotes tumorigenesis. PloS One, 2011, 6(5): e19785.
11. Jefferson JA, Simoni J, Escudero E, et al. Increased oxidative stress following acute and chronic high altitude exposure. High Alt Med Biol, 2004, 5(1): 61-69.
12. Aldashev AA, Kojonazarov BK, Amatov TA, et al. Phosphodiesterase type 5 and high altitude pulmonary hypertension. Thorax, 2005, 60(8): 683-687.
13. Gasche C, Chang CL, Rhees J, et al. Oxidative stress increases frame shift mutations in human colorectal cancer cells. Cancer Res, 2001, 61(20): 7444-7448.
14. Askew EW. Work at high altitude and oxidative stress: antioxidant nutrients. Toxicology, 2002, 180(2): 107-119.
15. Wu T, Kayser B. High altitude adaptation in Tibetans. High Alt Med Biol, 2006, 7(3): 193-208.
16. Beall CM. Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci USA, 2007, 104(Suppl 1): 8655-8660.
17. Chen QH, Ge RL, Wang XZ, et al. Exercise performance of Tibetan and Han adolescents at altitudes of 3,417 and 4,300 m. J Appl Physiol, (1985), 1997, 83(2): 661-667.
18. Beall CM. Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. Integr Comp Biol, 2006, 46(1): 18-24.
19. Beall CM. Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum Biol, 2000, 72(1): 201-228.
20. 陈万青, 邹小农, 李连弟, 等. 西藏自治区恶性肿瘤流行特征. 中国肿瘤, 2005, (6): 364-366.
21. 黎卫平, 陈超, 臧宝彩, 等. 西藏自治区拉萨市 2727 例恶性肿瘤发生顺位分析. 西藏大学学报 (自然科学版), 2011, 26(1): 52-55.
22. 德庆旺姆. 西藏地区藏族人群肺癌临床分析. 西藏科技, 2013, (11): 39-40.
23. Hayes DP. Cancer protection related to solar ultraviolet radiation, altitude and vitamin D. Med Hypotheses, 2010, 75(4): 378-382.
24. Bikle DD. Extraskeletal actions of vitamin D. Ann N Y Acad Sci, 2016, 1376(1): 29-52.
25. Hamra GB, Guha N, Cohen A, et al. Outdoor particulate matter exposure and lung cancer: a systematic review and meta-analysis. Environ Health Perspect, 2014, 122(9): 906-911.
26. Moen I, Stuhr LE. Hyperbaric oxygen therapy and cancer--a review. Target Oncol, 2012, 7(4): 233-242.
27. Hatfield SM, Kjaergaard J, Lukashev D, et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Trans Med, 2015, 7(277): 277ra230.
28. Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer, 2014, 14(11): 709-721.
29. Murray AJ, Horscroft JA. Mitochondrial function at extreme high altitude. J Physiol, 2016, 594(5): 1137-1149.
30. Semenza GL, Nejfelt MK, Chi SM, et al. Hypoxia-inducible nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene. Proc Natl Acad Sci USA, 1991, 88(13): 5680-5684.
31. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol, 1992, 12(12): 5447-5454.
32. Ema M, Taya S, Yokotani N, et al. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA, 1997, 94(9): 4273-4278.
33. Brown JM. Tumor hypoxia in cancer therapy. Methods Enzymol, 2007, 435: 297-321.
34. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev, 2007, 26(2): 225-239.
35. Zhao J, Du F, Shen G, et al. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis, 2015, 6: e1600.
36. Liu ZJ, Semenza GL, Zhang HF. Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B, 2015, 16(1): 32-43.
37. Manalo DJ, Rowan A, Lavoie T, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood, 2005, 105(2): 659-669.
38. Wong CC, Zhang H, Gilkes DM, et al. Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J Mol Med (Berlin, Germany), 2012, 90(7): 803-815.
39. Lanikova L, Reading NS, Hu H, et al. Evolutionary selected Tibetan variants of HIF pathway and risk of lung cancer. Oncotarget, 2017, 8(7): 11739-11747.
40. Woolcott OO, Castillo OA, Gutierrez C, et al. Inverse association between diabetes and altitude: a cross-sectional study in the adult population of the United States. Obesity (Silver Spring), 2014, 22(9): 2080-2090.
41. Woolcott OO, Gutierrez C, Castillo OA, et al. Inverse association between altitude and obesity: A prevalence study among andean and low-altitude adult individuals of Peru. Obesity (Silver Spring), 2016, 24(4): 929-937.
42. Duan W, Shen X, Lei J, et al. Hyperglycemia, a neglected factor during cancer progression. Biomed Res Int, 2014, 2014: 461917.
43. Woolcott OO, Ader M, Bergman RN. Glucose homeostasis during short-term and prolonged exposure to high altitudes. Endocr Rev, 2015, 36(2): 149-173.
44. Hensley CT, Faubert B, Yuan Q, et al. Metabolic Heterogeneity in Human Lung Tumors. Cell, 2016, 164(4): 681-694.
45. Labak CM, Wang PY, Arora R, et al. Glucose transport: meeting the metabolic demands of cancer, and applications in glioblastoma treatment. Am J Cancer Res, 2016, 6(8): 1599-1608.
46. Huang C, Freter C. Lipid metabolism, apoptosis and cancer therapy. Inter J Molecular Sci, 2015, 16(1): 924-949.
47. Hashmi S, Wang Y, Suman DS, et al. Human cancer: is it linked to dysfunctional lipid metabolism? Biochim Biophys Acta, 2015, 1850(2): 352-364.
48. Ackerman D, Simon MC. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol, 2014, 24(8): 472-478.
49. Stock C, Gassner B, Hauck CR, et al. Migration of human melanoma cells depends on extracellular pH and Na⁺/H⁺ exchange. J Physiol, 2005, 567(Pt 1): 225-238.
50. Ibrahim-Hashim A, Cornnell HH, Abrahams D, et al. Systemic buffers inhibit carcinogenesis in TRAMP mice. J Urol, 2012, 188(2): 624-631.
51. Azzarito T, Lugini L, Spugnini EP, et al. Effect of modified alkaline supplementation on syngenic melanoma growth in CB57/BL Mice. PloS One, 2016, 11(7): e0159763.
52. Robey IF, Nesbit LA. Investigating mechanisms of alkalinization for reducing primary breast tumor invasion. Biomed Res Int, 2013, 2013: 485196.
53. Swenson ER. Hypoxia and its acid-base consequences: from mountains to malignancy. Adv Exp Med Biol, 2016, 903: 301-323.
54. Wang JS, Wu CK. Systemic hypoxia affects exercise-mediated antitumor cytotoxicity of natural killer cells. J Appl Physiol (1985), 2009, 107(6): 1817-1824.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Current research status of Tibetan lung cancers

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