OpenLB
Open Library of Bioscience
Advanced Search
Journal of physiology and biochemistry
May, 2023;79 (2): 261-272.

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

Vanda Marques, Susana Ourô, Marta B Afonso, Cecília M P Rodrigues
Author Information
  1. Vanda Marques: Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal. ORCID
  2. Susana Ourô: Surgery Department, Hospital Beatriz Ângelo, Loures, Portugal. ORCID
  3. Marta B Afonso: Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal. ORCID
  4. Cecília M P Rodrigues: Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal. cmprodrigues@ff.ulisboa.pt. ORCID
PMID: 36495464 DOI: 10.1007/s13105-022-00936-y

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.

Keywords

Adipokines Chemoradiotherapy Rectal cancer STAT3 Stemness

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 [DOI: 10.7717/peerj.7624]
  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 [DOI: 10.1136/gut.2004.060533]
  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 [DOI: 10.4251/wjgo.v8.i5.416]
  5. Bardou M, Barkun AN, Martel M (2013) Obesity and colorectal cancer Gut 62:933–947. https://doi.org/10.1136/gutjnl-2013-304701 [DOI: 10.1136/gutjnl-2013-304701]
  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 [DOI: 10.1677/ERC-10-0083]
  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 [DOI: 10.3748/wjg.v25.i33.4945]
  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 [DOI: 10.1371/journal.Pone.0206542]
  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 [DOI: 10.1007/s00384-015-2231-9]
  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 [DOI: 10.1158/1078-0432.CCR-10-2257]
  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 [DOI: 10.1158/1940-6207.CAPR-15-0175]
  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 [DOI: 10.1245/s10434-016-5205-4]
  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 [DOI: 10.1016/j.canlet.2015.10.001]
  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 [DOI: 10.1016/S2468-1253(17)30074-2]
  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 [DOI: 10.1136/gut.2010.235754]
  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 [DOI: 10.1073/pnas.1114438109]
  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 [DOI: 10.1002/mc.20644]
  18. Frühbeck G (2006) Intracellular signalling pathways activated by leptin. Biochem J 393:7–20. https://doi.org/10.1042/BJ20051578 [DOI: 10.1042/BJ20051578]
  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 [DOI: 10.1136/gut.2008.159293]
  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 [DOI: 10.17235/reed.2020.7321/2020]
  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 [DOI: 10.1002/bjs.8732]
  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 [DOI: 10.1093/annonc/mdx224]
  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 [DOI: 10.1055/s-0031-1295686]
  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 [DOI: 10.1055/s-0037-1606116]
  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 [DOI: 10.1016/j.radonc.2020.06.023]
  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 [DOI: 10.1186/s12885-018-4997-y]
  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 [DOI: 10.1002/ijc.23821]
  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 [DOI: 10.1007/978-3-319-42542-9_2]
  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 [DOI: 10.1210/me.2009-0498]
  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 [DOI: 10.1016/j.biopha.2014.10.019]
  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 [DOI: 10.3892/ol.2018.9368]
  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 [DOI: 10.7150/ijbs.15438]
  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 [DOI: 10.1158/0008-5472.CAN-10-4660]
  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 [DOI: 10.2147/OTT.S157255]
  37. McCourt M, Armitage J, Monson JRT (2009) Rectal cancer. Surgeon 7:162–169. https://doi.org/10.1016/S1479-666X(09)80040-1 [DOI: 10.1016/S1479-666X(09)80040-1]
  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 [DOI: 10.1158/1055-9965.EPI-07-0708]
  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 [DOI: 10.1136/gutjnl-2012-302092]
  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 [DOI: 10.1136/jcp.2010.076414]
  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 [DOI: 10.1038/s41575-018-0038-1]
  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 [DOI: 10.1007/s00384-006-0181-y]
  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 [DOI: 10.1038/s41575-018-0069-7]
  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 [DOI: 10.3748/wjg.v16.i10.1252]
  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 [DOI: 10.3390/ph13090246]
  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 [DOI: 10.3389/fonc.2020.577653]
  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 [DOI: 10.1245/s10434-008-0221-7]
  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 [DOI: 10.1007/s11605-015-2987-9]
  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 [DOI: 10.1074/jbc.M312999200]
  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 [DOI: 10.1245/s10434-009-0617-z]
  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 [DOI: 10.1016/j.ejso.2005.09.010]
  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 [DOI: 10.3390/ijms23116040]
  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 [DOI: 10.1002/ijc.28429]
  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 [DOI: 10.3322/caac.21660]
  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 [DOI: 10.1016/j.orcp.2018.01.005]
  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 [DOI: 10.3892/ijo.2011.1105]
  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 [DOI: 10.1136/esmoopen-2020-000826]
  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 [DOI: 10.1097/DCR.0b013e31828e5a72]
  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 [DOI: 10.1007/s12038-011-9172-4]
  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 [DOI: 10.1097/MD.0000000000016190]
  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 [DOI: 10.3349/ymj.2018.59.1.35]
  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 [DOI: 10.1111/cas.14031]
  64. Zhang G, Li C, Liu Z et al (2016) Cancer stem cell targets – a review. Eur Rev Med Pharmacol Sci 20:2045–51 [PMID: 27249603]

MeSH Term

Humans
Carcinoembryonic Antigen
Adipokines
Adiponectin
Prognosis
Rectal Neoplasms
RNA, Messenger
Treatment Outcome

Chemicals

Carcinoembryonic Antigen
Adipokines
Adiponectin
RNA, Messenger
Journal Article
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0cancerCRTrectalleptinpatientsresponseadiponectinstemnessSTAT3non-responderspotentialserumexpressionlocallyadvancedbiomarkersadipokinesmightimpactmRNAevaluatedCEAp < 005levelscorrelatedAdipokinespatientResponsechemoradiotherapyhighlyvariableIdentificationdefiniteaccurateunmetneedsturncolorectaldevelopmenthypothesizedimbalancemodulatesPre-CRTtissuesamplescollectedcohortn = 33submittedlong-courseproctectomyAdiponectinmeasuredELISAtumourbiopsiesstemness-relatedgenesqRT-PCRtranscriptionfactorimmunoblottingCorrelationsclinicaldataaccuracyCarcinoembryonicantigendistinguishedrespondersHoweverhigherlowerassociatedpositiveextramesorectalnodesextramuralvascularinvasionfactorsinverselypositivelyphosphorylationpresentedsimilarresultstogetheractivationOCT4/KLF4accuratelyidentifiedAUROC080prognosisleptin/STAT3signallingaxisprovidesrationalbiomarkerpanelidentifieswillbenefittreatmentModulationoutcometherapyChemoradiotherapyRectalStemness

Similar Articles

Cited By (1)