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24 december 2024: Bron: GUT, BMJ journal

Uit een studie met 160 tumormonsters van patiënten met darmkanker blijkt dat vooral ultra bewerkt voedsel chronische ontstekingen in de darmen laat ontstaan en die ontstekingen op hun beurt laten darmkankertumoren ontstaan en doen eenmaal uitgegroeid tot een kwaadaardige tumor de darmkankertumoren groeien.

Volgens de onderzoekers onder leiding van prof. dr. Timothy Yeatman ontstaan de chronische ontstekingen via de zogeheten bioactieve lipidenen die ook komend uit gezonde voeding juist een goede rol kunnen spelen. Bioactieve lipidenen  zijn hele kleine moleculen die nauwelijks zichtbaar zijn maar wel actief in het laten ontstaan van ontstekingen als deze uit intensief bewerkte voeding in de darmen komt. Althans dat zegt prof. dr. Timothy Yeatman als toelichting op de publicatie van hun studie. 

“Bioactieve lipiden zijn piepkleine moleculen die afkomstig zijn van het voedsel dat we eten, en als deze moleculen uit bewerkte voedingsmiddelen komen, verstoren ze rechtstreeks het immuunsysteem en bevorderen ze chronische ontstekingen”, aldus prof. dr. Timothy Yeatman.

De onderzoekers gebruikten een specifieke gevoelige techniek voor het analyseren van de 160 tumormonsters van patiënten met darmkanker. De weggehaalde darmtumoren werden snel na de operatieve ingreep binnen een half uur  ingevroren en voor nadere analyse naar het laboratorium gebracht. In de darmtumoren vonden de onderzoekers veel moleculen die ontsteking bevorderend waren en een tekort aan moleculen die in het algemeen helpen ontstekingen op te lossen. 

Om dit probleem op te lossen adviseren voedingsdeskundigen om vooral visolie en Omega-3 vetzuren te gebruiken

Hier de Engelstalige toelichting over het belang van deze studie wat ik bewust niet heb vertaald om het niet al te ingewikkeld te maken:

WHAT THIS STUDY ADDS

  • Quantitative LC–MS/MS analysis of 81 human CRC and normal paired samples demonstrated a significant pro-inflammatory bias with little if any evidence of active, endogenous resolution of inflammation.

  • We demonstrated a marked defect in lipid class switching in CRC tumours with increased expression of genes encoding pro-inflammatory lipid mediators and their receptors, but absence or low expression of key resolving genes (ALOX15, EPHX1), as measured by quantitative reverse transcription-PCR, as a mechanism for the observed inflammatory bias. Moreover, we found that ineffective levels of PGE2/PGD2 (~70% of cases with T<N levels) and poor correlation with LXB4, as well as inefficient PGE2/PGD2 signalling (secondary to low PTGER2, 3, 4 levels in T vs N) may be responsible for defective lipid class switching.

  • scRNA-seq analysis identified tumour-associated macrophages in the TME as the source for many pro-inflammatory, lipid mediator producing genes. Spatial transcriptomics analysis of colon tumours showed a strong coexpression of ALOX5/ALOX5AP known to encode pro-inflammatory leucotrienes in high versus low LTB4 producing CRC tumour samples and decreased expression of some genes involved in the synthesis of PGE2, lipoxins, resolvins and other resolution mediators.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • In this study, we demonstrate that one of the most promising and often overlooked treatment options for CRC is related to harnessing the immune potential of TME.

  • CRCs have a clear pro-inflammatory bias leading to dysregulated eicosanoid pathway. This study suggests new therapeutic approaches for CRC could induce lipid class switching via production of endogenous specialised pro-resolving mediators (SPMs) (eg, CBD oil, AKBA, celastrol) or via provision of exogenous SPMs (eg, SPMs containing PDX and resolvins) that bypass deficiencies in ALOX12/15 to promote resolution of inflammation without immunosuppression. We believe that our findings are not limited to CRC, but are likely generalisable to many other tumour types.



Het volledige studierapport is gratis in te zien, klik daarvoor de titel van het abstract:

Colon
Original research
Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer
  1. Ramani Soundararajan1, 
  2. Michelle M Maurin1, 
  3. Jetsen Rodriguez-Silva1, 
  4. Gunjan Upadhyay2, 
  5. Ashley J Alden1, 
  6. Siddabasave Gowda B Gowda3, 
  7. Michael J Schell4, 
  8. Mingli Yang1, 
  9. Noah Jhad Levine5, 
  10. Divyavani Gowda3, 
  11. Punith M Sundaraswamy6, 
  12. Shu-Ping Hui3, 
  13. Lance Pflieger5, 
  14. Heiman Wang1, 
  15. Jorge Marcet7, 
  16. Carolina Martinez7, 
  17. Robert David Bennett7, 
  18. Allen Chudzinski7, 
  19. Andreas Karachristos7, 
  20. Timothy M Nywening8, 
  21. Paul M Cavallaro7, 
  22. Matthew Linley Anderson7, 
  23. Robert J Coffey9, 
  24. Michael V Nebozhyn10, 
  25. Andrey Loboda10, 
  26. Domenico Coppola11, 
  27. Warren Jackson Pledger12,13, 
  28. Ganesh Halade2, 
  29. Timothy J Yeatman1
  1. Correspondence to Professor Timothy J Yeatman; yeatman7383@gmail.com

Abstract

Background Over a century ago, Virchow proposed that cancer represents a chronically inflamed, poorly healing wound. Normal wound healing is represented by a transitory phase of inflammation, followed by a pro-resolution phase, with prostaglandin (PGE2/PGD2)-induced ‘lipid class switching’ producing inflammation-quenching lipoxins (LXA4, LXB4).

Objective We explored if lipid dysregulation in colorectal cancers (CRCs) is driven by a failure to resolve inflammation.

Design We performed liquid chromatography and tandem mass spectrometry (LC–MS/MS) untargeted analysis of 40 human CRC and normal paired samples and targeted, quantitative analysis of 81 human CRC and normal paired samples. We integrated analysis of lipidomics, quantitative reverse transcription-PCR, large scale gene expression, and spatial transcriptomics with public scRNASEQ data to characterize pattern, expression and cellular localisation of genes that produce and modify lipid mediators.

Results Targeted, quantitative LC–MS/MS demonstrated a marked imbalance of pro-inflammatory mediators, with a dearth of resolving lipid mediators. In tumours, we observed prominent over-expression of arachidonic acid derivatives, the genes encoding their synthetic enzymes and receptors, but poor expression of genes producing pro-resolving synthetic enzymes and resultant lipoxins (LXA4, LXB4) and associated receptors. These results indicate that CRC is the product of defective lipid class switching likely related to inadequate or ineffective levels of PGE2/PGD2.

Conclusion We show that the lipidomic profile of CRC tumours exhibits a distinct pro-inflammatory bias with a deficiency of endogenous resolving mediators secondary to defective lipid class switching. These observations pave the way for ‘resolution medicine’, a novel therapeutic approach for inducing or providing resolvins to mitigate the chronic inflammation driving cancer growth and progression.

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable as data is uploaded as supplementary information.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Colorectal cancer (CRC) is a complex disease characterised by the imbalance between proinflammatory and pro-resolving processes resulting in chronic inflammation akin to a poorly healing wound, with resultant immunosuppression and excessive cellular proliferation.

  • Lipid mediator class switching from arachidonic acid-based, pro-inflammatory mediators (leucotrienes) to specialised pro-resolving mediators has been identified as an essential mechanism for resolving inflammation in normal wound healing.

  • To date, studies that interrogate the cellular and molecular mechanisms that govern dysregulated CRC lipid metabolism and its impact on the immune tumour microenvironment (TME) are very limited.

WHAT THIS STUDY ADDS

  • Quantitative LC–MS/MS analysis of 81 human CRC and normal paired samples demonstrated a significant pro-inflammatory bias with little if any evidence of active, endogenous resolution of inflammation.

  • We demonstrated a marked defect in lipid class switching in CRC tumours with increased expression of genes encoding pro-inflammatory lipid mediators and their receptors, but absence or low expression of key resolving genes (ALOX15, EPHX1), as measured by quantitative reverse transcription-PCR, as a mechanism for the observed inflammatory bias. Moreover, we found that ineffective levels of PGE2/PGD2 (~70% of cases with T<N levels) and poor correlation with LXB4, as well as inefficient PGE2/PGD2 signalling (secondary to low PTGER2, 3, 4 levels in T vs N) may be responsible for defective lipid class switching.

  • scRNA-seq analysis identified tumour-associated macrophages in the TME as the source for many pro-inflammatory, lipid mediator producing genes. Spatial transcriptomics analysis of colon tumours showed a strong coexpression of ALOX5/ALOX5AP known to encode pro-inflammatory leucotrienes in high versus low LTB4 producing CRC tumour samples and decreased expression of some genes involved in the synthesis of PGE2, lipoxins, resolvins and other resolution mediators.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • In this study, we demonstrate that one of the most promising and often overlooked treatment options for CRC is related to harnessing the immune potential of TME.

  • CRCs have a clear pro-inflammatory bias leading to dysregulated eicosanoid pathway. This study suggests new therapeutic approaches for CRC could induce lipid class switching via production of endogenous specialised pro-resolving mediators (SPMs) (eg, CBD oil, AKBA, celastrol) or via provision of exogenous SPMs (eg, SPMs containing PDX and resolvins) that bypass deficiencies in ALOX12/15 to promote resolution of inflammation without immunosuppression. We believe that our findings are not limited to CRC, but are likely generalisable to many other tumour types.


Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable as data is uploaded as supplementary information.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and all experimental protocols were approved by the Institutional Review Board (IRB) of the University of South Florida. Informed consent was obtained for patients undergoing colorectal surgery at Tampa General Hospital (TGH) as per the approved IRB protocol for University of South Florida STUDY000356 prior to collection of deidentified matched tumour and normal mucosa samples.

Acknowledgments

We acknowledge Sarah E Glass for editorial assistance. The authors acknowledge the valuable support from Avennette Pinto, McKayla Carr and Ricardo Perez for helping with patient sample processing.

References

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