Abstract
Colorectal Cancer (CRC) is the third most leading cause of cancer related death worldwide and has a diverse clinical etiology. Mounting evidences has shown that CRC, in its rare yet lethal form as mucinous adenocarcinoma. Has led to poor prognosis and eventual complexity in the treatment. This subcategory of CRC characteristically secrete mucin hence, they are histologically identified based on the presence of mucin in CRC. In this context, the current article aims to provide a detailed overview and understanding of the underlying molecular mechanisms governing mucinous cancer onset and progression. We elaborate on the role of different pathways and molecular targets including microsatellite instability (MSI), chromosome instability (CIN) and CpG island methylator phenotype (CIMP), oncogenes such as KRAS, BRAF, p53 and p21 on mucinous CRC. The mucin genes, specifically MUC1, MUC4 and few other variants of the gel-secreted, transmembrane form of CRC play a vital role in the disease development. This makes the miRNA-mediated mucin regulations an exceptionally obliging aid in mucinous CRC understanding. The miRNAs discussed in context include miR-205, miR-373 and miR-124a to name a few. We further discuss the existing therapeutic strategies used to treat this variant of CRC. These diagnostic tools could help in the rapid identification and treatment of the disease.
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Agostini M, Pucciarelli S, Enzo MV, Del Bianco P, Briarava M, Bedin C, Maretto I, Friso ML, Lonardi S, Mescoli C, Toppan P (2011) Circulating cell-free DNA: a promising marker of pathologic tumor response in rectal cancer patients receiving preoperative chemoradiotherapy. Ann Surg Oncol 18:2461–2468
Braun MS, Richman SD, Adlard JW, Daly C, Turner F, Barrett J, Seymour MT (2006) Association of topoisomerase-1 (Topo1) with the efficacy of chemotherapy in a randomized trial for advanced colorectal cancer patients (FOCUS). J Clin Oncol 24:10009–10009
Buecher B, Cacheux W, Rouleau E, Dieumegard B, Mitry E, Lièvre A (2013) Role of microsatellite instability in the management of colorectal cancers. Dig Liver Dis 45:441–449
Chand M, Yu S, Swift RI, Brown G (2014) Mucinous carcinoma of the rectum: a distinct clinicopathological entity. Tech Coloproctol 18:335–344
Chang KH, Miller N, Kheirelseid EA, Lemetre C, Ball GR, Smith MJ, Regan M, McAnena OJ, Kerin MJ (2011) MicroRNA signature analysis in colorectal cancer: identification of expression profiles in stage II tumors associated with aggressive disease. Int J Colorectal Dis 11:1415–1422
Clarke CN, Kopetz ES (2015) BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. J Gastrointest Oncol 6:660–667
Deng G, Kakar S, Kim YS (2011) MicroRNA-124a and microRNA-34b/c are frequently methylated in all histological types of colorectal cancer and polyps, and in the adjacent normal mucosa. Oncol Lett 1:175–180
Duncan TJ, Watson NF, Al-Attar AH, Scholefield JH, Durrant LG (2007) The role of MUC1 and MUC3 in the biology and prognosis of colorectal cancer. World J Surg Oncol 5:31–42
El-Sayed IH, Lotfy M, Moawad M (2011) Immunodiagnostic potential of mucin (MUC2) and Thomsen-Friedenreich (TF) antigens in Egyptian patients with colorectal cancer. Eur Rev Med Pharmacol Sci 15:91–97
Eyking A, Reis H, Frank M, Gerken G, Schmid KW, Cario E (2016) MiR-205 and MiR-373 are associated with aggressive human mucinous colorectal cancer. PLoS One 6:e0156871
Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Preisinger AC, Thomas G, Kinzler KW (1990) Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247:49–56
Fransen K, Klintenas M, Österström A, Dimberg J, Monstein HJ, Söderkvist P (2004) Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis 25:527–533
Fu Z, Huang J, Guo L (2012) Mucinous adenocarcinoma of the colon pathological characters and CT image analysis. Chin J Mod Drug Appl 04:24
Garcia-Aguilar J, Chen Z, Smith DD, Li W, Madoff RD, Cataldo P, Marcet J, Pastor C (2012) Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer. Ann Surg 254:486–492
Glasgow SC, Yu J, Carvalho LP, Shannon WD, Fleshman JW, McLeod HL (2005) Unfavourable expression of pharmacologic markers in mucinous colorectal cancer. Br J Cancer 92:259–264
Grothey A, Tabernero J, Arnold D, De Gramont A, Ducreux MP, O'Dwyer PJ, Van Cutsem E, Bosanac I, Srock S, Mancao C, Gilberg F (2018) Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): findings from cohort 2 of MODUL—A multicentre, randomized trial of biomarker-driven maintenance treatment following first-line induction therapy. Ann Oncol 29:714–715
Halvorsen TB, Seim E (1988) Influence of mucinous components on survival in colorectal adenocarcinomas: a multivariate analysis. J Clin Pathol 41:1068–1072
Hsu HP, Lai MD, Lee JC, Yen MC, Weng TY, Chen WC, Fang JH, Chen YL (2017) Mucin 2 silencing promotes colon cancer metastasis through interleukin-6 signaling. Sci Rep 7:5823
Hugen N, Brown G, Glynne-Jones R, de Wilt JH, Nagtegaal ID (2016) Advances in the care of patients with mucinous colorectal cancer. Nat Rev Clin Oncol 13:361–369
Kim MJ, Park JS, Park SI, Kim NK, Kim JH, Moon HJ (2003) Accuracy in differentiation of mucinous and nonmucinous rectal carcinoma on MR imaging. J Comput Assist Tomogr 27:48–55
Kim M, Goicochea L, Fang SH (2016) Case report: collision tumour of colon leiomyosarcoma and adenocarcinoma. J Clin Diagn Res 6:PD03–PPD4
Ko EY, Ha HK, Kim AY, Yoon KH, Yoo CS, Kim HC, Kim JC (2007) CT differentiation of mucinous and nonmucinous colorectal carcinoma. AJR Am J Roentgenol 3:785–791
Kocer B, Soran A, Erdogan S, Karabeyoglu M, Yildirim O, Eroglu A, Bozkurt B, Cengiz O (2002) Expression of MUC5AC in colorectal carcinoma and relationship with prognosis. Pathol Int 52:470–477
Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A (2007) Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 370:135–142
Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, Antonini NF, Punt CJ, Van Krieken JH (2009) Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 100:266–273
Kopetz S, Grothey A, Yaeger R (2019) Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 381:1632–1643
Krishn SR, Batra SK, Kaur S (2015) Advances in miRNA-mediated mucin regulation. Curr Pharmacol Rep 6:355–364
Lagger G, Doetzlhofer A, Schuettengruber B, Haidweger E, Simboeck E, Tischler J, Chiocca S, Suske G, Rotheneder H, Wintersberger E, Seiser C (2003) The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene. Mol Cell Biol 23:2669–2679
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520
Liu X, Feng D, Huo X, **ao X, Chen Z (2019) Association of intron microsatellite status and exon mutational profiles of TP53 in human colorectal cancer. Exp Ther Med 18:4287–4294
Luo H, Zhao Q, Wei W, Zheng L, Yi S, Li G, Wang W, Sheng H, Pu H, Mo H, Zuo Z (2020) Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer. Sci Transl Med 12:eaax7533
Malki A, ElRuz RA, Gupta I, Allouch A, Vranic S, Al Moustafa AE (2021) Molecular mechanisms of colon cancer progression and metastasis: recent insights and advancements. Int J Mol Sci 22:130–153
Mukherjee P, Pathangey LB, Bradley JB, Tinder TL, Basu GD, Akporiaye ET, Gendler SJ (2007) MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model. Vaccine 25:1607–1618
Park JS, Huh JW, Park YA, Cho YB, Yun SH, Kim HC, Lee WY, Chun HK (2015) Prognostic comparison between mucinous and nonmucinous adenocarcinoma in colorectal cancer. Medicine 94:e658
Pino MS, Chung DC (2010) The chromosomal instability pathway in colon cancer. Gastroenterology 138:2059–2072
Popper HH (2017) Cons: the confusing mucinous adenocarcinoma classification. Transl Lung Cancer Res 2:234–240
Porru M, Pompili L, Caruso C, Biroccio A, Leonetti C (2018) Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res 37:57–67
Pothuraju R, Rachagani S, Krishn SR, Chaudhary S, Nimmakayala RK, Siddiqui JA, Ganguly K, Lakshmanan I, Cox JL, Mallya K, Kaur S (2020) Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance. Mol Cancer 19:37–51
Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A 97:10014–10019
Rizzo S, Bronte G, Fanale D, Corsini L, Silvestris N, Santini D, Gulotta G, Bazan V, Gebbia N, Fulfaro F, Russo A (2010) Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy? Cancer Treat Rev 36:S56
Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, Dietrich D, Biesmans B, Bodoky G, Barone C, Aranda E (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 28:466–474
Saif MW, Chu E (2010) Biology of colorectal cancer. Cancer J 3:196–201
Shanmugam C, Jhala NC, Katkoori VR, Wan W, Meleth S, Grizzle WE, Manne U (2010) Prognostic value of mucin 4 expression in colorectal adenocarcinomas. Cancer 116:3577–3586
Strickler JH, Hurwitz HI (2012) Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. Oncologist 17:513–524
Tanaka H, Deng G, Matsuzaki K, Kakar S, Kim GE, Miura S, Sleisenger MH, Kim YS (2006) BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non-mucinous colorectal cancer. Int J Cancer 118:2765–2771
Thrumurthy SG, Thrumurthy SS, Gilbert CE, Ross P, Haji A (2010) Colorectal adenocarcinoma: risks, prevention and diagnosis. BMJ 354:i3590
Umetani N, Kim J, Hiramatsu S, Reber HA, Hines OJ, Bilchik AJ, Hoon DS (2006) Increased integrity of free circulating DNA in sera of patients with colorectal or periampullary cancer: direct quantitative PCR for ALU repeats. Clin Chem 52:1062–1069
Vymetalkova V, Pardini B, Rosa F, Jiraskova K, Di Gaetano C, Bendova P, Levy M, Veskrnova V, Buchler T, Vodickova L, Naccarati A (2017) Polymorphisms in microRNA binding sites of mucin genes as predictors of clinical outcome in colorectal cancer patients. Carcinogenesis 1:28–39
Wang G, Fu Y, Hu F, Lan J, Xu F, Yang X, Luo X, Wang J, Hu J (2017) Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway. Cell Death Dis 8:e2607
Wilson AJ, Byun DS, Popova N, Murray LB, L’Italien K, Sowa Y, Arango D, Velcich A, Augenlicht LH, Mariadason JM (2006) Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J Biol Chem 281:13548–13558
Xu X, Wells A, Padilla MT, Kato K, Kim KC, Lin Y (2014) A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance. Carcinogenesis 35:2457–2466
Yang YC, Wang D, ** L, Yao HW, Zhang JH, Wang J, Zhao XM, Shen CY, Chen W, Wang XL, Shi R (2018) Circulating tumor DNA detectable in early- and late-stage colorectal cancer patients. Biosci Rep 38:BSR20180322
Acknowledgments
The authors are thankful to Chettinad Academy of Research and Education (CARE) for providing the infrastructural support and to SERB-DST (project number: EMR/2017/001877), Govt. of India, for providing support to complete this piece of work.
Authors’ Contributions
SP and XFS, HZ were involved in the conception of the study and designed the study protocol, and wrote the manuscript. HG, MMK, and AB wrote parts of the manuscript. SP, HG, and MMK were involved in designing the images. SP, AB, HZ, and XFS critically reviewed the manuscript. All authors read, reviewed, and approved the final manuscript.
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The authors declare no conflicts of interest.
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Ganesan, H., Makalakshmi, M.K., Banerjee, A., Zhang, H., Sun, XF., Pathak, S. (2022). Mucinous Colorectal Cancer Oxidative Stress and Therapeutic MicroRNAs. In: Chakraborti, S. (eds) Handbook of Oxidative Stress in Cancer: Therapeutic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-16-1247-3_85-1
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DOI: https://doi.org/10.1007/978-981-16-1247-3_85-1
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