Skip to main content

Advertisement

SpringerLink
Log in

Modulation of rectal cancer stemness, patient outcome and therapy response by adipokines

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer is highly variable. Identification of CRT non-responders and definite accurate biomarkers of response are unmet needs. In turn, adipokines might impact on colorectal cancer development. We hypothesized that imbalance in leptin and adiponectin modulates stemness potential CRT response in rectal cancer. Pre-CRT serum and tissue samples were collected from a cohort of locally advanced rectal cancer patients (n = 33), submitted to long-course CRT and proctectomy. Adiponectin and leptin were measured by ELISA in serum. In tumour biopsies, mRNA expression of stemness-related genes was evaluated by qRT-PCR and transcription factor STAT3 by immunoblotting. Correlations with clinical data and accuracy of potential CRT response biomarkers were evaluated. Carcinoembryonic antigen (CEA) but not leptin or adiponectin distinguished CRT responders from non-responders (p < 0.05). However, higher leptin and lower adiponectin serum levels were associated with positive extramesorectal nodes and extramural vascular invasion. mRNA expression of stemness factors was inversely correlated with adiponectin but positively correlated with leptin. STAT3 phosphorylation presented similar results. CEA levels together with STAT3 activation and OCT4/KLF4 expression accurately identified rectal cancer patients, CRT non-responders (AUROC 0.80; p < 0.05). Adipokines might impact rectal cancer stemness and patient prognosis. The leptin/STAT3 signalling axis provides the rational for a potential biomarker panel that identifies rectal cancer patients who will not benefit from CRT treatment.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The data that support the current study are available within the article, supplementary materials and from the corresponding author upon reasonable request.

References

  1. Al-Shibli SM, Harun N, Ashour AE et al (2019) Expression of leptin and leptin receptors in colorectal cancer—an immunohistochemical study. PeerJ 7:e7624. https://doi.org/10.7717/peerj.7624

    Article  PubMed  PubMed Central  Google Scholar 

  2. Amemori S, Ootani A, Aoki S, et al (2007) Adipocytes and preadipocytes promote the proliferation of colon cancer cells in vitro. Am J Physiol Hear Circ Physiol 292. https://doi.org/10.1152/ajpgi.00145.2006

  3. Aparicio T, Kotelevets L, Tsocas A et al (2005) Leptin stimulates the proliferation of human colon cancer cells in vitro but does not promote the growth of colon cancer xenografts in nude mice or intestinal tumorigenesis in ApcMin/+ mice. Gut 54:1136–1145. https://doi.org/10.1136/gut.2004.060533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Azizian A, Gruber J, Ghadimi BM, Gaedcke J (2016) MicroRNA in rectal cancer. World J Gastrointest Oncol 8:416–426. https://doi.org/10.4251/wjgo.v8.i5.416

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bardou M, Barkun AN, Martel M (2013) Obesity and colorectal cancer Gut 62:933–947. https://doi.org/10.1136/gutjnl-2013-304701

    Article  CAS  PubMed  Google Scholar 

  6. Bartucci M, Svensson S, Ricci-Vitiani L et al (2010) Obesity hormone leptin induces growth and interferes with the cytotoxic effects of 5-fluorouracil in colorectal tumor stem cells. Endocr Relat Cancer 17:823–833. https://doi.org/10.1677/ERC-10-0083

    Article  CAS  PubMed  Google Scholar 

  7. Cai D, Huang Z, Yu H et al (2019) Prognostic value of preoperative carcinoembryonic antigen/tumor size in rectal cancer. World J Gastroenterol 25:4945–4958. https://doi.org/10.3748/wjg.v25.i33.4945

    Article  PubMed  PubMed Central  Google Scholar 

  8. Campayo M, Navarro A, JC B et al (2018) Predictive response signature for preoperative chemoradiotherapy in rectal cancer. Inl J Colorectal Dis 13:e0206542. https://doi.org/10.1371/journal.Pone.0206542

    Article  Google Scholar 

  9. Caramés C, Cristóbal I, Moreno V et al (2015) MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer. Int J Colorectal Dis 30:899–906. https://doi.org/10.1007/s00384-015-2231-9

    Article  PubMed  Google Scholar 

  10. Casado E, García VM, Sánchez JJ et al (2011) A combined strategy of SAGE and quantitative PCR provides a 13-gene signature that predicts preoperative chemoradiotherapy response and outcome in rectal cancer. Clin Cancer Res 17:4145–4154. https://doi.org/10.1158/1078-0432.CCR-10-2257

    Article  CAS  PubMed  Google Scholar 

  11. Chong DQ, Mehta RS, Song M et al (2015) Prediagnostic plasma adiponectin and survival among patients with colorectal cancer. Cancer Prev Res 8:1138–1145. https://doi.org/10.1158/1940-6207.CAPR-15-0175

    Article  CAS  Google Scholar 

  12. Chow OS, Kuk D, Keskin M et al (2016) KRAS and combined KRAS/TP53 mutations in locally advanced rectal cancer are independently associated with decreased response to neoadjuvant therapy. Ann Surg Oncol 23:2548–2555. https://doi.org/10.1245/s10434-016-5205-4

    Article  PubMed  PubMed Central  Google Scholar 

  13. DeClercq V, McMurray DN, Chapkin RS (2015) Obesity promotes colonic stem cell expansion during cancer initiation. Cancer Lett 369:336–343. https://doi.org/10.1016/j.canlet.2015.10.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dossa F, Chesney TR, Acuna SA, Baxter NN (2017) A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2:501–513. https://doi.org/10.1016/S2468-1253(17)30074-2

    Article  PubMed  Google Scholar 

  15. Endo H, Hosono K, Uchiyama T et al (2011) Leptin acts as a growth factor for colorectal tumours at stages subsequent to tumour initiation in murine colon carcinogenesis. Gut 60:1363–1371. https://doi.org/10.1136/gut.2010.235754

    Article  CAS  PubMed  Google Scholar 

  16. Feldman DE, Chen C, Punj V et al (2012) Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells. Proc Natl Acad Sci U S A 109:829–834. https://doi.org/10.1073/pnas.1114438109

    Article  PubMed  Google Scholar 

  17. Fenton JI, Birmingham JM (2010) Adipokine regulation of colon cancer: adiponectin attenuates interleukin-6-induced colon carcinoma cell proliferation via STAT-3. Mol Carcinog 49:700–709. https://doi.org/10.1002/mc.20644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Frühbeck G (2006) Intracellular signalling pathways activated by leptin. Biochem J 393:7–20. https://doi.org/10.1042/BJ20051578

    Article  CAS  PubMed  Google Scholar 

  19. Fujisawa T, Endo H, Tomimoto A et al (2008) Adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition. Gut 57:1531–1538. https://doi.org/10.1136/gut.2008.159293

    Article  CAS  PubMed  Google Scholar 

  20. Gago T, Caldeira P, Cunha AC et al (2021) Can we optimize CEA as a response marker in rectal cancer? Rev Esp Enfermedades Dig 113:423–428. https://doi.org/10.17235/reed.2020.7321/2020

    Article  Google Scholar 

  21. Global Cancer Observatory: Cancer Tomorrow (2022) Lyon, Fr. Int. Agency Res. Cancer. Available from https://gco.iarc.fr/tomorrow/. Accessed Jan 2022

  22. Global Cancer Observatory: Causes (2022) Lyon, Fr. Int. Agency Res. Cancer. Available from https://gco.iarc.fr/causes/obesity/. Accessed Jan 2022

  23. Glynne-Jones R, Hughes R (2012) Critical appraisal of the “wait and see” approach in rectal cancer for clinical complete responders after chemoradiation. Br J Surg 99:897–909. https://doi.org/10.1002/bjs.8732

    Article  CAS  PubMed  Google Scholar 

  24. Glynne-Jones R, Wyrwicz L, Tiret E et al (2017) Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28:iv22–iv40. https://doi.org/10.1093/annonc/mdx224

    Article  CAS  PubMed  Google Scholar 

  25. Gribovskaja-Rupp I, Kosinski L, Ludwig KA (2011) Obesity and colorectal cancer. Clin Colon Rectal Surg 24:229–243. https://doi.org/10.1055/s-0031-1295686

    Article  PubMed  PubMed Central  Google Scholar 

  26. Habr-Gama A, São Julião GP, Vailati BB et al (2017) Management of the complete clinical response. Clin Colon Rectal Surg 30:387–394. https://doi.org/10.1055/s-0037-1606116

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hsu YC, Luo CW, Huang WL et al (2020) BMI1-KLF4 axis deficiency improves responses to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer. Radiother Oncol 149:249–258. https://doi.org/10.1016/j.radonc.2020.06.023

    Article  CAS  PubMed  Google Scholar 

  28. Hu H, Zhang J, Cai Y et al (2018) CEA clearance pattern as a predictor for pathologic complete response after neoadjuvant chemoradiation for rectal cancer: results of the FOWARC trial. J Clin Oncol 18:1145. https://doi.org/10.1186/s12885-018-4997-y

    Article  CAS  Google Scholar 

  29. Jaffe T, Schwartz B (2008) Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal-transduction pathways. Int J Cancer 123:2543–2556. https://doi.org/10.1002/ijc.23821

    Article  CAS  PubMed  Google Scholar 

  30. Jochem C, Leitzmann M (2016) Obesity and colorectal cancer. Recent results Cancer Res 208:17–41. https://doi.org/10.1007/978-3-319-42542-9_2

    Article  CAS  PubMed  Google Scholar 

  31. Kim AY, Lee YS, Kim KH et al (2010) Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation. Mol Endocrinol 24:1441–1452. https://doi.org/10.1210/me.2009-0498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kozovska Z, Gabrisova V, Kucerova L (2014) Colon cancer: cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother 68:911–916. https://doi.org/10.1016/j.biopha.2014.10.019

    Article  CAS  PubMed  Google Scholar 

  33. Li J, Liu YY, Yang XF et al (2018) Effects and mechanism of STAT3 silencing on the growth and apoptosis of colorectal cancer cells. Oncol Lett 16:5575–5582. https://doi.org/10.3892/ol.2018.9368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li Y, Wang J, Ma X et al (2016) A review of neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Int J Biol Sci 12:1022–1031. https://doi.org/10.7150/ijbs.15438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lin L, Liu A, Peng Z et al (2011) STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res 71:7226–7237. https://doi.org/10.1158/0008-5472.CAN-10-4660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lu W, Huang Z, Li N, Liu H (2018) Low circulating total adiponectin, especially its non-high-molecular weight fraction, represents a promising risk factor for colorectal cancer: a meta-analysis. Onco Targets Ther 11:2519–2531. https://doi.org/10.2147/OTT.S157255

    Article  PubMed  PubMed Central  Google Scholar 

  37. McCourt M, Armitage J, Monson JRT (2009) Rectal cancer. Surgeon 7:162–169. https://doi.org/10.1016/S1479-666X(09)80040-1

    Article  CAS  PubMed  Google Scholar 

  38. Moghaddam AA, Woodward M, Huxley R (2007) Obesity and risk of colorectal cancer: a meta-analysis of 31 studies with 70,000 events. Cancer Epidemiol Biomarkers Prev 16:2533–2547. https://doi.org/10.1158/1055-9965.EPI-07-0708

    Article  PubMed  Google Scholar 

  39. Moon HS, Liu X, Nagel JM et al (2013) Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice. Gut 62:561–570. https://doi.org/10.1136/gutjnl-2012-302092

    Article  CAS  PubMed  Google Scholar 

  40. Monnien F, Zaki H, Borg C et al (2010) Prognostic value of phosphorylated STAT3 in advanced rectal cancer: a study from 104 French patients included in the EORTC 22921 trial. J Clin Pathol 63:873–878. https://doi.org/10.1136/jcp.2010.076414

    Article  PubMed  Google Scholar 

  41. Mullen M, Gonzalez-Perez RR (2016) Leptin-induced JAK/STAT signaling and cancer growth. Vaccines 4. https://doi.org/10.3390/vaccines4030026

  42. Murphy N, Jenab M, Gunter MJ (2018) Adiposity and gastrointestinal cancers: epidemiology, mechanisms and future directions. Nat Rev Gastroenterol Hepatol 15:659–670. https://doi.org/10.1038/s41575-018-0038-1

    Article  CAS  PubMed  Google Scholar 

  43. Ogunwobi OO, Beales ILP (2007) The anti-apoptotic and growth stimulatory actions of leptin in human colon cancer cells involves activation of JNK mitogen activated protein kinase, JAK2 and PI3 kinase/Akt. Int J Colorectal Dis 22:401–409. https://doi.org/10.1007/s00384-006-0181-y

    Article  PubMed  Google Scholar 

  44. O’Sullivan J, Lysaght J, Donohoe CL, Reynolds JV (2018) Obesity and gastrointestinal cancer: the interrelationship of adipose and tumour microenvironments. Nat Rev Gastroenterol Hepatol 15:699–714. https://doi.org/10.1038/s41575-018-0069-7

    Article  PubMed  Google Scholar 

  45. Otake S, Takeda H, Fujishima S et al (2010) Decreased levels of plasma adiponectin associated with increased risk of colorectal cancer. World J Gastroenterol 16:1252–1257. https://doi.org/10.3748/wjg.v16.i10.1252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ourô S, Mourato C, Ferreira MP et al (2020) Evaluation of tissue and circulating mir-21 as potential biomarker of response to chemoradiotherapy in rectal cancer. Pharmaceuticals 13:1–14. https://doi.org/10.3390/ph13090246

    Article  CAS  Google Scholar 

  47. Ourô S, Mourato C, Velho S et al (2020) Potential of miR-21 to predict incomplete response to chemoradiotherapy in rectal adenocarcinoma. Front Oncol 10:577653. https://doi.org/10.3389/fonc.2020.577653

    Article  PubMed  PubMed Central  Google Scholar 

  48. Paik SS, Jang SM, Jang KS et al (2009) Leptin expression correlates with favorable clinicopathologic phenotype and better prognosis in colorectal adenocarcinoma. Ann Surg Oncol 16:297–303. https://doi.org/10.1245/s10434-008-0221-7

    Article  PubMed  Google Scholar 

  49. Probst CP, Becerra AZ, Aquina CT et al (2016) Watch and wait?—Elevated pretreatment CEA is associated with decreased pathological complete response in rectal cancer. J Gastrointest Surg 20:43–52. https://doi.org/10.1007/s11605-015-2987-9

    Article  PubMed  Google Scholar 

  50. Rouet-Benzineb P, Aparicio T, Guilmeau S et al (2004) Leptin counteracts sodium butyrate-induced apoptosis in human colon cancer HT-29 cells via NF-κB signaling. J Biol Chem 279:16495–16502. https://doi.org/10.1074/jbc.M312999200

    Article  CAS  PubMed  Google Scholar 

  51. Saigusa S, Tanaka K, Toiyama Y et al (2009) Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 16:3488–3498. https://doi.org/10.1245/s10434-009-0617-z

    Article  PubMed  Google Scholar 

  52. Smith FM, Reynolds JV, Miller N et al (2006) Pathological and molecular predictors of the response of rectal cancer to neoadjuvant radiochemotherapy. Eur J Surg Oncol 32:55–64. https://doi.org/10.1016/j.ejso.2005.09.010

    Article  CAS  PubMed  Google Scholar 

  53. Smolskas E, Mikulskytė G, Sileika E et al (2022) Tissue-based markers as a tool to assess response to neoadjuvant radiotherapy in rectal cancer—systematic review. Int J Mol Sci 23:6040. https://doi.org/10.3390/ijms23116040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Spitzner M, Roesler B, Bielfeld C et al (2014) STAT3 inhibition sensitizes colorectal cancer to chemoradiotherapy in vitro and in vivo. Int J Cancer 134:997–1007. https://doi.org/10.1002/ijc.28429

    Article  CAS  PubMed  Google Scholar 

  55. Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660

    Article  PubMed  Google Scholar 

  56. Tarasiuk A, Mosińska P, Fichna J (2018) The mechanisms linking obesity to colon cancer: an overview. Obes Res Clin Pract 12:251–259. https://doi.org/10.1016/j.orcp.2018.01.005

    Article  PubMed  Google Scholar 

  57. Uchiyama T, Takahashi H, Endo H et al (2011) Role of the long form leptin receptor and of the STAT3 signaling pathway in colorectal cancer progression. Int J Oncol 39:935–940. https://doi.org/10.3892/ijo.2011.1105

    Article  CAS  PubMed  Google Scholar 

  58. Vecchione L, Stintzing S, Pentheroudakis G et al (2020) ESMO management and treatment adapted recommendations in the COVID-19 era: colorectal cancer. ESMO Open 5:e000826. https://doi.org/10.1136/esmoopen-2020-000826

    Article  PubMed  Google Scholar 

  59. Wallin U, Rothenberger D, Lowry A et al (2013) CEA – a predictor for pathologic complete response after neoadjuvant therapy for rectal cancer. Dis Colon Rectum 56:859–868. https://doi.org/10.1097/DCR.0b013e31828e5a72

    Article  PubMed  Google Scholar 

  60. Wang D, Chen J, Chen H et al (2012) Leptin regulates proliferation and apoptosis of colorectal carcinoma through PI3K/Akt/mTOR signalling pathway. J Biosci 37:91–101. https://doi.org/10.1007/s12038-011-9172-4

    Article  CAS  PubMed  Google Scholar 

  61. Yu J, Lee SH, Jeung TS, Chang HK (2019) Expression of vascular endothelial growth factor as a predictor of complete response for preoperative chemoradiotherapy in rectal cancer. Medicine (Baltimore) 98:e16190. https://doi.org/10.1097/MD.0000000000016190

    Article  PubMed  Google Scholar 

  62. You L, Guo X, Huang Y (2018) Correlation of cancer stem-cell markers OCT4, SOX2, and NANOG with clinicopathological features and prognosis in operative patients with rectal cancer. Yonsei Med J 59:35–42. https://doi.org/10.3349/ymj.2018.59.1.35

    Article  CAS  PubMed  Google Scholar 

  63. Zhang BD, Li YR, Ding LD et al (2019) Loss of PTPN4 activates STAT3 to promote the tumor growth in rectal cancer. Cancer Sci 110:2258–2272. https://doi.org/10.1111/cas.14031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang G, Li C, Liu Z et al (2016) Cancer stem cell targets – a review. Eur Rev Med Pharmacol Sci 20:2045–51

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the Mediagnost GmbH (Reutlingen, Germany) for providing easy access to the ELISA kits used in this work.

Funding

This work was supported by the Fundação para a Ciência e Tecnologia (PTDC/MED-FAR/3492/2021 and PD/BD/135467/2017) and by European Horizon 2020 (H2020-MSCA-RISE-2016–734719).

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal

    Vanda Marques, Marta B. Afonso & Cecília M. P. Rodrigues

  2. Surgery Department, Hospital Beatriz Ângelo, Loures, Portugal

    Susana Ourô

  3. Hospital da Luz, Lisbon, Portugal

    Susana Ourô

Authors
  1. Vanda Marques
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susana Ourô
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marta B. Afonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cecília M. P. Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

VM performed experimental work and statistical analysis and wrote the manuscript. SO collected patient samples, curated clinical data and revised the manuscript. MBA contributed to manuscript writing. CMPR was responsible for funding and revised the manuscript. All authors contributed to the experimental design, revision and approval of the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Cecília M. P. Rodrigues.

Ethics declarations

Ethics approval

The study was conducted in accordance with the Declaration of Helsinki and approved by the institution’s Ethical Committee (Comissão de Ética para a Saúde do Hospital Beatriz Ângelo, Project Identification Number 0240) on 13 March 2017. The study was registered in the Portuguese Data Protection Agency (Comissão Nacional de Protecção de Dados) on 27 January 2017.

Informed consent

Informed consent was obtained from all subjects involved in the study.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

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

Key Points

• To date there are no validated biomarkers of CRT response in rectal cancer.

• Adipokines modulate cancer stemness impacting on patient prognosis and therapy response.

• Leptin/STAT3 signalling axis plays a role in CRT resistance.

• Combination of STAT3, KLF4, OCT4 and CEA allows accurate identification of CRT non-responders.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 273 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

Marques, V., Ourô, S., Afonso, M.B. et al. Modulation of rectal cancer stemness, patient outcome and therapy response by adipokines. J Physiol Biochem 79, 261–272 (2023). https://doi.org/10.1007/s13105-022-00936-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-022-00936-y

Keywords

Search

Navigation