Research progress on biomarkers of pulmonary lymphangioleiomyomatosis_West China Medical Journal

Authors：

LI Mengli ¹ , MIN Li ¹ , ZHANG Xiaoli ² , SHEN Shijun ² ,  LEI Wen ¹

1. Department of Respiratory Medicine, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P. R. China;
2. Graduate School, Kunming Medical University, Kunming, Yunnan 650101, P. R. China;

Corresponding author：

LEI Wen, Email: leiwenkm@163.com

Keywords：

Pulmonary lymphangioleiomyomatosis; Biomarkers; Prognostic evaluation

DOI：

10.7507/1002-0179.202004479

Video：

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Pulmonary lymphangioleiomyomatosis (PLAM) is a rare chronic multi-system neoplastic disease that occurs in women of childbearing age. It lacks specific clinical manifestations and requires reliable biomarkers to achieve precise management. In recent years, with the emergence of emerging biomarkers, the detection rate of PLAM has been significantly improved, which can better monitor disease progression and provide timely feedback on the efficacy. These emerging biomarkers mainly include vascular endothelial growth factor-D, vitamin D-binding protein, CT score and prostaglandins. This article will focus on the current research results, and summarize the research progress of emerging biomarkers in PLAM diagnosis, prognosis evaluation, and disease monitoring, aiming to provide new ideas for the research and treatment of PLAM.

Citation： LI Mengli, MIN Li, ZHANG Xiaoli, SHEN Shijun, LEI Wen. Research progress on biomarkers of pulmonary lymphangioleiomyomatosis. West China Medical Journal, 2021, 36(1): 110-113. doi: 10.7507/1002-0179.202004479 Copy

1.	Wang Q, Luo M, Xiang B, et al. The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis. Respir Res, 2020, 21(1): 55.
2.	Ataya A, Brantly M, Riley L. Lymphangioleiomyomatosis (LAM). Am J Respir Crit Care Med, 2018, 198(4): P7-P8.
3.	Ataya A, Riley L, Brantly ML. Serum vascular endothelial growth factor D in cystic lung disease. JAMA, 2019, 321(4): 401-402.
4.	Freitas CSG, Baldi BG, Jardim C, et al. Pulmonary hypertension in lymphangioleiomyomatosis: prevalence, severity and the role of carbon monoxide diffusion capacity as a screening method. Orphanet J Rare Dis, 2017, 12(1): 74.
5.	Gupta N, Henske EP. Pulmonary manifestations in tuberous sclerosis complex. Am J Med Genet C Semin Med Genet, 2018, 178(3): 326-337.
6.	廖新, 况九龙. 血管内皮生长因子-D 对淋巴管平滑肌瘤病诊治价值的研究进展. 中国呼吸与危重监护杂志, 2019, 18(6): 603-605.
7.	Miller S, Coveney C, Johnson J, et al. The vitamin D binding protein axis modifies disease severity in lymphangioleiomyomatosis. Eur Respir J, 2018, 52(5): 1800951.
8.	Gopalakrishnan V, Yao J, Steagall WK, et al. Use of CT imaging to quantify progression and response to treatment in lymphangioleiomyomatosis. Chest, 2019, 155(5): 962-971.
9.	Li C, Zhang E, Sun Y, et al. Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis. PLoS One, 2014, 9(10): e104809.
10.	Achen MG, Jeltsch M, Kukk E, et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A, 1998, 95(2): 548-553.
11.	Gupta N, Finlay GA, Kotloff RM, et al. Lymphangioleiomyomatosis diagnosis and management: high-resolution chest computed tomography, transbronchial lung biopsy, and pleural disease management. an official American Thoracic Society/Japanese Respiratory Society clinical practice guideline. Am J Respir Crit Care Med, 2017, 196(10): 1337-1348.
12.	Nascimento ECTD, Baldi BG, Mariani AW, et al. Immunohistological features related to functional impairment in lymphangioleiomyomatosis. Respir Res, 2018, 19(1): 83.
13.	McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med, 2016, 194(6): 748-761.
14.	Hirose M, Matsumuro A, Arai T, et al. Serum vascular endothelial growth factor-D as a diagnostic and therapeutic biomarker for lymphangioleiomyomatosis. PLoS One, 2019, 14(2): e0212776.
15.	Amaral AF, de Oliveira MR, Dias OM, et al. Concentration of serum vascular endothelial growth factor (VEGF-D) and its correlation with functional and clinical parameters in patients with lymphangioleiomyomatosis from a brazilian reference center. Lung, 2019, 197(2): 139-146.
16.	Mou Y, Ye L, Wang J, et al. Diagnostic and treatment monitoring potential of serum vascular endothelial growth factor-D in lymphangioleiomyomatosis. Lymphology, 2016, 49(3): 140-149.
17.	Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell, 2017, 168(6): 960-976.
18.	Lamattina AM, Taveira-Dasilva A, Goldberg HJ, et al. Circulating biomarkers from the phase 1 trial of sirolimus and autophagy inhibition for patients with lymphangioleiomyomatosis. Chest, 2018, 154(5): 1070-1082.
19.	Kurosaki T, Otani S, Miyoshi K, et al. Favorable survival even with high disease-specific complication rates in lymphangioleiomyomatosis after lung transplantation-long-term follow-up of a Japanese center. Clin Respir J, 2020, 14(2): 116-123.
20.	Zhan Y, Shen L, Xu W, et al. Functional improvements in patients with lymphangioleiomyomatosis after sirolimus: an observational study. Orphanet J Rare Dis, 2018, 13(1): 34.
21.	Taveira-DaSilva AM, Jones AM, Julien-Williams P, et al. Long-term effect of sirolimus on serum vascular endothelial growth factor D levels in patients with Lymphangioleiomyomatosis. Chest, 2018, 153(1): 124-132.
22.	Lisowska-Myjak B, Jóźwiak-Kisielewska A, Łukaszkiewicz J, et al. Vitamin D-binding protein as a biomarker to confirm specific clinical diagnoses. Expert Rev Mol Diagn, 2020, 20(1): 49-56.
23.	冯娟, 夏维波. 维生素 D 结合蛋白研究进展. 国际内分泌代谢杂志, 2016, 36(3): 209-213.
24.	Bouillon R, Schuit F, Antonio L, et al. Vitamin D binding protein: a historic overview. Front Endocrinol (Lausanne), 2020, 10: 910.
25.	Chishimba L, Thickett DR, Stockley RA, et al. The vitamin D axis in the lung: a key role for vitamin D-binding protein. Thorax, 2010, 65(5): 456-462.
26.	Gupta N, Vassallo R, Wikenheiser-Brokamp KA, et al. Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med, 2015, 191(12): 1354-1366.
27.	Henske EP, Jóźwiak S, Kingswood JC, et al. Tuberous sclerosis complex. Nat Rev Dis Primers, 2016, 2: 16035.
28.	Logginidou H, Ao X, Russo I, et al. Frequent estrogen and progesterone receptor immunoreactivity in renal angiomyolipomas from women with pulmonary lymphangioleiomyomatosis. Chest, 2000, 117(1): 25-30.
29.	Li C, Li N, Liu X, et al. Proapoptotic protein Bim attenuates estrogen-enhanced survival in lymphangioleiomyomatosis. JCI Insight, 2016, 1(19): e86629.
30.	Jeong Y, Swami S, Krishnan AV, et al. Inhibition of mouse breast tumor-initiating cells by calcitriol and dietary vitamin D. Mol Cancer Ther, 2015, 14(8): 1951-1961.
31.	Liu HJ, Henske EP. Vitamin D binding protein: a new biomarker of disease severity in lymphangioleiomyomatosis. Eur Respir J, 2018, 52(5): 1801886.
32.	Nijmeh J, El-Chemaly S, Henske EP. Emerging biomarkers of lymphangioleiomyomatosis. Expert Rev Respir Med, 2018, 12(2): 95-102.
33.	Kim SH, Baek MS, Yoon DS, et al. Vitamin D inhibits expression and activity of matrix metalloproteinase in human lung fibroblasts (HFL-1) cells. Tuberc Respir Dis (Seoul), 2014, 77(2): 73-80.
34.	Kim C, Do KH, Cha J, et al. Effects of sirolimus in lymphangioleiomyomatosis patients on lung cysts and pulmonary function: long-term follow-up observational study. Eur Radiol, 2020, 30(2): 735-743.
35.	Doubková M, Štefániková M, Čan V, et al. Lymphangioleiomyomatosis. Klin Onkol, 2019, 32(5): 367-374.
36.	Larsen TC, Hasani AM, Rollison SF, et al. Clinical CT underestimation of the percentage volume occupied by cysts in patients with lymphangioleiomyomatosis. Clin Imaging, 2020, 59(2): 119-125.
37.	Yao J, Taveira-DaSilva AM, Colby TV, et al. CT grading of lung disease in lymphangioleiomyomatosis. AJR Am J Roentgenol, 2012, 199(4): 787-793.
38.	Lynn E, O’Callaghan M, Sahadevan A, et al. Emerging approaches to predict prognosis and monitor disease progression in lymphangioleiomyomatosis. Am J Respir Crit Care Med, 2019, 200(11): 1424-1426.
39.	Hu-Wang E, Schuzer JL, Rollison S, et al. Chest CT scan at radiation dose of a posteroanterior and lateral chest radiograph series: a proof of principle in lymphangioleiomyomatosis. Chest, 2019, 155(3): 528-533.
40.	Li C, Liu X, Liu Y, et al. Tuberin regulates prostaglandin receptor-mediated viability, via rheb, in mTORC1-hyperactive cells. Mol Cancer Res, 2017, 15(10): 1318-1330.
41.	Lu Y, Liu X, Zhang E, et al. Estrogen activates pyruvate kinase M2 and increases the growth of TSC2-deficient cells. PLoS One, 2020, 15(2): e0228894.
42.	姚懿雯, 李冬. 前列腺素 E 受体在抑制人肺巨噬细胞炎性反应中的作用. 基础医学与临床, 2019, 39(1): 90-91.
43.	Li C, Lee PS, Sun Y, et al. Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med, 2014, 211(1): 15-28.

1. Wang Q, Luo M, Xiang B, et al. The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis. Respir Res, 2020, 21(1): 55.
2. Ataya A, Brantly M, Riley L. Lymphangioleiomyomatosis (LAM). Am J Respir Crit Care Med, 2018, 198(4): P7-P8.
3. Ataya A, Riley L, Brantly ML. Serum vascular endothelial growth factor D in cystic lung disease. JAMA, 2019, 321(4): 401-402.
4. Freitas CSG, Baldi BG, Jardim C, et al. Pulmonary hypertension in lymphangioleiomyomatosis: prevalence, severity and the role of carbon monoxide diffusion capacity as a screening method. Orphanet J Rare Dis, 2017, 12(1): 74.
5. Gupta N, Henske EP. Pulmonary manifestations in tuberous sclerosis complex. Am J Med Genet C Semin Med Genet, 2018, 178(3): 326-337.
6. 廖新, 况九龙. 血管内皮生长因子-D 对淋巴管平滑肌瘤病诊治价值的研究进展. 中国呼吸与危重监护杂志, 2019, 18(6): 603-605.
7. Miller S, Coveney C, Johnson J, et al. The vitamin D binding protein axis modifies disease severity in lymphangioleiomyomatosis. Eur Respir J, 2018, 52(5): 1800951.
8. Gopalakrishnan V, Yao J, Steagall WK, et al. Use of CT imaging to quantify progression and response to treatment in lymphangioleiomyomatosis. Chest, 2019, 155(5): 962-971.
9. Li C, Zhang E, Sun Y, et al. Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis. PLoS One, 2014, 9(10): e104809.
10. Achen MG, Jeltsch M, Kukk E, et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A, 1998, 95(2): 548-553.
11. Gupta N, Finlay GA, Kotloff RM, et al. Lymphangioleiomyomatosis diagnosis and management: high-resolution chest computed tomography, transbronchial lung biopsy, and pleural disease management. an official American Thoracic Society/Japanese Respiratory Society clinical practice guideline. Am J Respir Crit Care Med, 2017, 196(10): 1337-1348.
12. Nascimento ECTD, Baldi BG, Mariani AW, et al. Immunohistological features related to functional impairment in lymphangioleiomyomatosis. Respir Res, 2018, 19(1): 83.
13. McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med, 2016, 194(6): 748-761.
14. Hirose M, Matsumuro A, Arai T, et al. Serum vascular endothelial growth factor-D as a diagnostic and therapeutic biomarker for lymphangioleiomyomatosis. PLoS One, 2019, 14(2): e0212776.
15. Amaral AF, de Oliveira MR, Dias OM, et al. Concentration of serum vascular endothelial growth factor (VEGF-D) and its correlation with functional and clinical parameters in patients with lymphangioleiomyomatosis from a brazilian reference center. Lung, 2019, 197(2): 139-146.
16. Mou Y, Ye L, Wang J, et al. Diagnostic and treatment monitoring potential of serum vascular endothelial growth factor-D in lymphangioleiomyomatosis. Lymphology, 2016, 49(3): 140-149.
17. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell, 2017, 168(6): 960-976.
18. Lamattina AM, Taveira-Dasilva A, Goldberg HJ, et al. Circulating biomarkers from the phase 1 trial of sirolimus and autophagy inhibition for patients with lymphangioleiomyomatosis. Chest, 2018, 154(5): 1070-1082.
19. Kurosaki T, Otani S, Miyoshi K, et al. Favorable survival even with high disease-specific complication rates in lymphangioleiomyomatosis after lung transplantation-long-term follow-up of a Japanese center. Clin Respir J, 2020, 14(2): 116-123.
20. Zhan Y, Shen L, Xu W, et al. Functional improvements in patients with lymphangioleiomyomatosis after sirolimus: an observational study. Orphanet J Rare Dis, 2018, 13(1): 34.
21. Taveira-DaSilva AM, Jones AM, Julien-Williams P, et al. Long-term effect of sirolimus on serum vascular endothelial growth factor D levels in patients with Lymphangioleiomyomatosis. Chest, 2018, 153(1): 124-132.
22. Lisowska-Myjak B, Jóźwiak-Kisielewska A, Łukaszkiewicz J, et al. Vitamin D-binding protein as a biomarker to confirm specific clinical diagnoses. Expert Rev Mol Diagn, 2020, 20(1): 49-56.
23. 冯娟, 夏维波. 维生素 D 结合蛋白研究进展. 国际内分泌代谢杂志, 2016, 36(3): 209-213.
24. Bouillon R, Schuit F, Antonio L, et al. Vitamin D binding protein: a historic overview. Front Endocrinol (Lausanne), 2020, 10: 910.
25. Chishimba L, Thickett DR, Stockley RA, et al. The vitamin D axis in the lung: a key role for vitamin D-binding protein. Thorax, 2010, 65(5): 456-462.
26. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, et al. Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med, 2015, 191(12): 1354-1366.
27. Henske EP, Jóźwiak S, Kingswood JC, et al. Tuberous sclerosis complex. Nat Rev Dis Primers, 2016, 2: 16035.
28. Logginidou H, Ao X, Russo I, et al. Frequent estrogen and progesterone receptor immunoreactivity in renal angiomyolipomas from women with pulmonary lymphangioleiomyomatosis. Chest, 2000, 117(1): 25-30.
29. Li C, Li N, Liu X, et al. Proapoptotic protein Bim attenuates estrogen-enhanced survival in lymphangioleiomyomatosis. JCI Insight, 2016, 1(19): e86629.
30. Jeong Y, Swami S, Krishnan AV, et al. Inhibition of mouse breast tumor-initiating cells by calcitriol and dietary vitamin D. Mol Cancer Ther, 2015, 14(8): 1951-1961.
31. Liu HJ, Henske EP. Vitamin D binding protein: a new biomarker of disease severity in lymphangioleiomyomatosis. Eur Respir J, 2018, 52(5): 1801886.
32. Nijmeh J, El-Chemaly S, Henske EP. Emerging biomarkers of lymphangioleiomyomatosis. Expert Rev Respir Med, 2018, 12(2): 95-102.
33. Kim SH, Baek MS, Yoon DS, et al. Vitamin D inhibits expression and activity of matrix metalloproteinase in human lung fibroblasts (HFL-1) cells. Tuberc Respir Dis (Seoul), 2014, 77(2): 73-80.
34. Kim C, Do KH, Cha J, et al. Effects of sirolimus in lymphangioleiomyomatosis patients on lung cysts and pulmonary function: long-term follow-up observational study. Eur Radiol, 2020, 30(2): 735-743.
35. Doubková M, Štefániková M, Čan V, et al. Lymphangioleiomyomatosis. Klin Onkol, 2019, 32(5): 367-374.
36. Larsen TC, Hasani AM, Rollison SF, et al. Clinical CT underestimation of the percentage volume occupied by cysts in patients with lymphangioleiomyomatosis. Clin Imaging, 2020, 59(2): 119-125.
37. Yao J, Taveira-DaSilva AM, Colby TV, et al. CT grading of lung disease in lymphangioleiomyomatosis. AJR Am J Roentgenol, 2012, 199(4): 787-793.
38. Lynn E, O’Callaghan M, Sahadevan A, et al. Emerging approaches to predict prognosis and monitor disease progression in lymphangioleiomyomatosis. Am J Respir Crit Care Med, 2019, 200(11): 1424-1426.
39. Hu-Wang E, Schuzer JL, Rollison S, et al. Chest CT scan at radiation dose of a posteroanterior and lateral chest radiograph series: a proof of principle in lymphangioleiomyomatosis. Chest, 2019, 155(3): 528-533.
40. Li C, Liu X, Liu Y, et al. Tuberin regulates prostaglandin receptor-mediated viability, via rheb, in mTORC1-hyperactive cells. Mol Cancer Res, 2017, 15(10): 1318-1330.
41. Lu Y, Liu X, Zhang E, et al. Estrogen activates pyruvate kinase M2 and increases the growth of TSC2-deficient cells. PLoS One, 2020, 15(2): e0228894.
42. 姚懿雯, 李冬. 前列腺素 E 受体在抑制人肺巨噬细胞炎性反应中的作用. 基础医学与临床, 2019, 39(1): 90-91.
43. Li C, Lee PS, Sun Y, et al. Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med, 2014, 211(1): 15-28.

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