Skip to main content

Advertisement

SpringerLink
Log in

Perturbations in inflammatory pathways are associated with shortness of breath profiles in oncology patients receiving chemotherapy

  • Research
  • Published:
Supportive Care in Cancer Aims and scope Submit manuscript

Abstract

Purpose

One plausible mechanistic hypothesis is the potential contribution of inflammatory mechanisms to shortness of breath. This study was aimed to evaluate for associations between the occurrence of shortness of breath and perturbations in inflammatory pathways.

Methods

Patients with cancer reported the occurrence of shortness of breath six times over two cycles of chemotherapy. Latent class analysis was used to identify subgroups of patients with distinct shortness of breath occurrence profiles (i.e., none (70.5%), decreasing (8.2%), increasing (7.8%), high (13.5%)). Using an extreme phenotype approach, whole transcriptome differential gene expression and pathway impact analyses were performed to evaluate for perturbed signaling pathways associated with shortness of breath between the none and high classes. Two independent samples (RNA-sequencing (n = 293) and microarray (n = 295) methodologies) were evaluated. Fisher’s combined probability method was used to combine these results to obtain a global test of the null hypothesis. In addition, an unweighted knowledge network was created using the specific pathway maps to evaluate for interconnections among these pathways.

Results

Twenty-nine Kyoto Encyclopedia of Genes and Genomes inflammatory signaling pathways were perturbed. The mitogen-activated protein kinase signaling pathway node had the highest closeness, betweenness, and degree scores. In addition, five common respiratory disease-related pathways, that may share mechanisms with cancer-related shortness of breath, were perturbed.

Conclusions

Findings provide preliminary support for the hypothesis that inflammation contribute to the occurrence of shortness of breath in patients with cancer. In addition, the mechanisms that underlie shortness of breath in oncology patients may be similar to other respiratory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Data will be provided to the publisher after they obtain a material transfer agreement from the University of California, San Francisco. Individuals who would like a copy of the survey can contact the corresponding author.

References

  1. Hui D, Bohlke K, Bao T, Campbell TC, Coyne PJ, Currow DC, Gupta A, Leiser AL, Mori M, Nava S, Reinke LF, Roeland EJ, Seigel C, Walsh D, Campbell ML (2021) Management of dyspnea in advanced cancer: ASCO guideline. J Clin Oncol 39(12):1389–1411. https://doi.org/10.1200/JCO.20.03465

    Article  PubMed  Google Scholar 

  2. Undem BJ, Nassenstein C (2009) Airway nerves and dyspnea associated with inflammatory airway disease. Respir Physiol Neurobiol 167(1):36–44. https://doi.org/10.1016/j.resp.2008.11.012

    Article  PubMed  Google Scholar 

  3. Barnes PJ, Celli BR (2009) Systemic manifestations and comorbidities of COPD. Eur Respir J 33(5):1165. https://doi.org/10.1183/09031936.00128008

    Article  CAS  PubMed  Google Scholar 

  4. Bracci L, Schiavoni G, Sistigu A, Belardelli F (2014) Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 21(1):15–25. https://doi.org/10.1038/cdd.2013.67

    Article  CAS  PubMed  Google Scholar 

  5. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L (2018) Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9(6):7204–7218. https://doi.org/10.18632/oncotarget.23208

    Article  PubMed  Google Scholar 

  6. Rivera MP, Detterbeck FC, Socinski MA, Moore DT, Edelman MJ, Jahan TM, Ansari RH, Luketich JD, Peng G, Monberg M, Obasaju CK, Gralla RJ (2009) Impact of preoperative chemotherapy on pulmonary function tests in resectable early-stage non-small cell lung cancer. Chest 135(6):1588–1595. https://doi.org/10.1378/chest.08-1430

    Article  PubMed  Google Scholar 

  7. Ji Y, Li M, Chang M, Liu R, Qiu J, Wang K, Deng C, Shen Y, Zhu J, Wang W, Xu L, Sun H (2022) Inflammation: roles in skeletal muscle atrophy. Antioxidants (Basel) 11(9):1686. https://doi.org/10.3390/antiox11091686

    Article  CAS  PubMed  Google Scholar 

  8. Bruera E, Schmitz B, Pither J, Neumann CM, Hanson J (2000) The frequency and correlates of dyspnea in patients with advanced cancer. J Pain Symptom Manag 19(5):357–362. https://doi.org/10.1016/s0885-3924(00)00126-3

    Article  CAS  Google Scholar 

  9. Gilliam LA, Moylan JS, Callahan LA, Sumandea MP, Reid MB (2011) Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy. Muscle Nerve 43(1):94–102. https://doi.org/10.1002/mus.21809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Currow DC, Quinn S, Ekstrom M, Kaasa S, Johnson MJ, Somogyi AA, Klepstad P (2015) Can variability in the effect of opioids on refractory breathlessness be explained by genetic factors? BMJ Open 5(5):e006818. https://doi.org/10.1136/bmjopen-2014-006818

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rausch SM, Clark MM, Patten C, Liu H, Felten S, Li Y, Sloan J, Yang P (2010) Relationship between cytokine gene single nucleotide polymorphisms and symptom burden and quality of life in lung cancer survivors. Cancer 116(17):4103–4113. https://doi.org/10.1002/cncr.25255

    Article  CAS  PubMed  Google Scholar 

  12. Su T, Sun H, Lu X, He C, Xiao L, He J, Yang Y, Tang Y (2020) Genetic polymorphisms and haplotypes of BRCA1 gene associated with quality of life and survival among patients with non-small-cell lung cancer. Qual Life Res 29(10):2631–2640

    Article  PubMed  Google Scholar 

  13. Shin J, Kober KM, Wong ML, Yates P, Cooper BA, Paul SM, Hammer M, Conley Y, Levine JD, Miaskowski C (2023) Distinct shortness of breath profiles in oncology outpatients undergoing chemotherapy. J Pain Symptom Manage 65(3):242–255. https://doi.org/10.1016/j.jpainsymman.2022.11.010

    Article  PubMed  Google Scholar 

  14. Koutrouli M, Karatzas E, Paez-Espino D, Pavlopoulos GA (2020) A guide to conquer the biological network era using graph theory. Front Bioeng Biotechnol 8:34. https://doi.org/10.3389/fbioe.2020.00034

    Article  PubMed  PubMed Central  Google Scholar 

  15. Portenoy RK, Thaler HT, Kornblith AB, McCarthy Lepore J, Friedlander-Klar H, Kiyasu E, Sobel K, Coyle N, Kemeny N, Norton L, Scher H (1994) The memorial symptom assessment scale: an instrument for the evaluation of symptom prevalence, characteristics and distress. Eur J Cancer 30(9):1326–1336. https://doi.org/10.1016/0959-8049(94)90182-1

    Article  Google Scholar 

  16. Team RC (2019) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria

    Google Scholar 

  17. Kober KM, Harris C, Conley YP, Dhruva A, Dokiparthi V, Hammer MJ, Levine JD, Oppegaard K, Paul S, Shin J, Sucher A, Wright F, Yuen B, Olshen AB, Miaskowski C (2022) Perturbations in common and distinct inflammatory pathways associated with morning and evening fatigue in outpatients receiving chemotherapy. Cancer Med 12(6):7369–7380. https://doi.org/10.1002/cam4.5435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26(1):139–140. https://doi.org/10.1093/bioinformatics/btp616

    Article  CAS  PubMed  Google Scholar 

  19. Smyth GK, Ritchie M, Thorne N, Wettenhall J (2005) LIMMA: linear models for microarray data. In: Bioinformatics and computational biology solutions using R and bioconductor. Statistics for Biology and Health

    Google Scholar 

  20. Leek JT, Storey JD (2007) Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 3(9):1724–1735. https://doi.org/10.1371/journal.pgen.0030161

    Article  CAS  PubMed  Google Scholar 

  21. Draghici S, Khatri P, Tarca AL, Amin K, Done A, Voichita C, Georgescu C, Romero R (2007) A systems biology approach for pathway level analysis. Genome Res 17(10):1537–1545. https://doi.org/10.1101/gr.6202607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Aoki-Kinoshita KF, Kanehisa M (2007) Gene annotation and pathway mapping in KEGG. Methods Mol Biol 396:71–91. https://doi.org/10.1007/978-1-59745-515-2_6

    Article  CAS  PubMed  Google Scholar 

  23. Fisher RA (1925) Statistical methods for research workers. Oliver and Boyd, Edinburgh

    Google Scholar 

  24. Dunn OJ (1961) Multiple comparisons among means. J Am Stat Assoc 56(293):52–64. https://doi.org/10.1080/01621459.1961.10482090

    Article  Google Scholar 

  25. Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K (2017) KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 45(D1):D353–Dd61. https://doi.org/10.1093/nar/gkw1092

    Article  CAS  PubMed  Google Scholar 

  26. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Newman M (2018) Chapter 7 - Measures and metrics. Networks: Oxford University Press, pp 158–217

    Book  Google Scholar 

  28. Cooper GM (2000) In: The cell: a molecular approach [Internet]. Sinauer Associates, Sunderland (MA) Available from: https://www.ncbi.nlm.nih.gov/books/NBK9839/

    Google Scholar 

  29. Newton R, Holden NS (2006) New aspects of p38 mitogen activated protein kinase (MAPK) biology in lung inflammation. Drug Discov Today Dis Mech 3(1):53–61. https://doi.org/10.1016/j.ddmec.2006.02.007

    Article  PubMed  PubMed Central  Google Scholar 

  30. Halu A, Liu S, Baek SH, Hobbs BD, Hunninghake GM, Cho MH, Silverman EK, Sharma A (2019) Exploring the cross-phenotype network region of disease modules reveals concordant and discordant pathways between chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Hum Mol Genet 28(14):2352–2364. https://doi.org/10.1093/hmg/ddz069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu J, Wang F, Luo F (2023) The role of JAK/STAT pathway in fibrotic diseases: molecular and cellular mechanisms. Biomolecules 13(1):119. https://doi.org/10.3390/biom13010119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hwang JA, Kim D, Chun S-M, Bae S, Song JS, Kim MY, Koo HJ, Song JW, Kim WS, Lee JC, Kim HR, Choi C-M, Jang SJ (2018) Genomic profiles of lung cancer associated with idiopathic pulmonary fibrosis. J Pathol 244(1):25–35. https://doi.org/10.1002/path.4978

    Article  CAS  PubMed  Google Scholar 

  33. Wang J, Hu K, Cai X, Yang B, He Q, Wang J, Weng Q (2022) Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis. Acta Pharm Sin B 12(1):18–32. https://doi.org/10.1016/j.apsb.2021.07.023

    Article  CAS  PubMed  Google Scholar 

  34. Schuliga M (2015) NF-kappaB signaling in chronic inflammatory airway disease. Biomolecules 5(3):1266–1283. https://doi.org/10.3390/biom5031266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. He M, Zhang Y, Xie F, Dou X, Han M, Zhang H (2018) Role of PI3K/Akt/NF-κB and GSK-3β pathways in the rat model of cardiopulmonary bypass-related lung injury. Biomed Pharmacother 106:747–754. https://doi.org/10.1016/j.biopha.2018.06.125

    Article  CAS  PubMed  Google Scholar 

  36. Kim ME, Kim DH, Lee JS (2022) FoxO transcription factors: applicability as a novel immune cell regulators and therapeutic targets in oxidative stress-related diseases. Int J Mol Sci 23(19):11877. https://doi.org/10.3390/ijms231911877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Al-Tamari HM, Dabral S, Schmall A, Sarvari P, Ruppert C, Paik J, DePinho RA, Grimminger F, Eickelberg O, Guenther A, Seeger W, Savai R, Pullamsetti SS (2018) FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis. EMBO Mol Med 10(2):276–293. https://doi.org/10.15252/emmm.201606261

    Article  CAS  PubMed  Google Scholar 

  38. Culley FJ (2009) Natural killer cells in infection and inflammation of the lung. Immunology 128(2):151–163. https://doi.org/10.1111/j.1365-2567.2009.03167.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cahilog Z, Zhao H, Wu L, Alam A, Eguchi S, Weng H, Ma D (2020) The role of neutrophil NETosis in organ injury: novel inflammatory cell death mechanisms. Inflammation 43(6):2021–2032. https://doi.org/10.1007/s10753-020-01294-x

    Article  PubMed  Google Scholar 

  40. Balamayooran T, Balamayooran G, Jeyaseelan S (2010) Review: Toll-like receptors and NOD-like receptors in pulmonary antibacterial immunity. Innate Immun 16(3):201–210. https://doi.org/10.1177/1753425910366058

    Article  CAS  PubMed  Google Scholar 

  41. Tomankova T, Kriegova E, Liu M (2015) Chemokine receptors and their therapeutic opportunities in diseased lung: far beyond leukocyte trafficking. Am J Phys Lung Cell Mol Phys 308(7):L603–LL18. https://doi.org/10.1152/ajplung.00203.2014

    Article  CAS  Google Scholar 

  42. Atamas SP, Chapoval SP, Keegan AD (2013) Cytokines in chronic respiratory diseases. F1000 Biol Rep 5:3. https://doi.org/10.3410/b5-3

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kuwano K (2007) Epithelial cell apoptosis and lung remodeling. Cell Mol Immunol 4(6):419–429

    CAS  PubMed  Google Scholar 

  44. Zayet S, Kadiane-Oussou NJ, Lepiller Q, Zahra H, Royer PY, Toko L, Gendrin V, Klopfenstein T (2020) Clinical features of COVID-19 and influenza: a comparative study on Nord Franche-Comte cluster. Microbes Infect 22(9):481–488. https://doi.org/10.1016/j.micinf.2020.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Anatol Sucher and Brian Yuen managed the storage and processing of the biospecimens. This study extends work previously published as part of Joosun Shin’s PhD dissertation.

Funding

This study was supported by grants from the National Cancer Institute (CA134900 and CA233774). Ms. Shin was supported by research grants from Oncology Nursing Foundation and International Society of Nurses in Genetics. Dr. Olshen is supported by grants UCSF NCI Cancer Center Support Grant (CA082103) and UCSF-CTSI (NCATS UL1 TR000004).

Author information

Authors and Affiliations

  1. School of Nursing, University of California, 2 Koret Way – N631Y, San Francisco, CA, 94143-0610, USA

    Joosun Shin, Christine Miaskowski, Vasuda Dokiparthi, Bruce Cooper, Steven Paul & Kord Kober

  2. Dana-Farber Cancer Institute, Boston, MA, USA

    Joosun Shin & Marilyn J. Hammer

  3. School of Medicine, University of California, San Francisco, CA, USA

    Christine Miaskowski, Melisa L. Wong & Jon D. Levine

  4. Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia

    Patsy Yates

  5. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

    Adam B. Olshen

  6. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    Christine Miaskowski, Adam B. Olshen, Ritu Roy & Kord Kober

  7. School of Nursing, Univeristy of Pittsburgh, 3500 Victoria St, Pittsburgh, 15213, PA, USA

    Yvette P. Conley

Authors
  1. Joosun Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine Miaskowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melisa L. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patsy Yates
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adam B. Olshen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ritu Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vasuda Dokiparthi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bruce Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Steven Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yvette P. Conley
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jon D. Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marilyn J. Hammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kord Kober
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Joosun Shin: Conceptualization; Investigation; Funding acquisition; Writing - original draft; Methodology; Visualization; Formal analysis; Validation; Writing - review & editing. Christine Miaskowski: Supervision; Writing - original draft; Writing - review & editing; Methodology; Conceptualization; Funding acquisition; Project administration; Resources; Investigation. Melisa L. Wong: Writing - review & editing; Supervision. Patsy Yates: Writing - review & editing; Supervision. Adam Olshen: Methodology; Writing - review & editing; Formal analysis. Roy Ritu: Formal analysis; Writing - review & editing. Vasuda Dokiparthi: Writing - review & editing; Formal analysis. Steven Paul: Writing - review & editing; Formal analysis. Bruce Cooper: Formal analysis; Writing - review & editing. Yvette Conley: Methodology; Writing - review & editing. Jon D. Levine: Writing - review & editing; Methodology. Marilyn J. Hammer: Writing - review & editing; Methodology. Kord Kober: Conceptualization; Funding acquisition; Writing - original draft; Writing - review & editing; Visualization; Validation; Methodology; Formal analysis; Data curation; Supervision; Software; Investigation; Project administration; Resources.

Corresponding author

Correspondence to Kord Kober.

Ethics declarations

Ethical approval

This study was approved by the Committee on Human Research at the University of California.

Consent to participate

This study was exempted from written informed consent.

Consent for publication

All of the authors read the final version of the paper and approved its submission for publication.

Competing interests

Dr. Wong reported conflicts of interest outside of the submitted work: An immediate family member is an employee of Genentech with stock ownership and Dr. Wong receives royalties from UpToDate. The remaining authors have no conflicts of interest to declare.

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(DOCX 57 kb)

ESM 2

(DOCX 36 kb)

ESM 3

(DOCX 37 kb)

ESM 4

(DOCX 49.1 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, J., Miaskowski, C., Wong, M.L. et al. Perturbations in inflammatory pathways are associated with shortness of breath profiles in oncology patients receiving chemotherapy. Support Care Cancer 32, 250 (2024). https://doi.org/10.1007/s00520-024-08446-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00520-024-08446-x

Keywords

Search

Navigation