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Resistance to Cell Death in Mucinous Colorectal Cancer—A Review

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Resistance to Cell Death in Mucinous Colorectal Cancer—A Review cancers Review Resistance to Cell Death in Mucinous Colorectal Cancer—A Review Emer O’Connell 1,2, Ian S. Reynolds 1,2 , Deborah A. McNamara 1,3, John P. Burke 1 and Jochen H. M. Prehn 2,4,* 1 Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland; [email protected] (E.O.); [email protected] (I.S.R.); [email protected] (D.A.M.); [email protected] (J.P.B.) 2 Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland 3 Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland 4 Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland * Correspondence: [email protected] Simple Summary: Mucinous colorectal cancer is characterised by abundant mucin glycoprotein production and is associated with resistance to chemotherapy-based treatments. This review outlines mechanisms for cell death resistance present in mucinous colorectal cancer including glycoprotein in- teractions with cell survival and cell apoptotic pathways. Further mechanisms are explored, including alterations in the expression of chemotherapy metabolism and resistance genes. This review identifies directions for future investigation of mucinous colorectal cancer and novel treatment strategies. Abstract: Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10–15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite Citation: O’Connell, E.; instability and the CpG island methylator phenotype. Mutations of the APC gene and p53 mutations Reynolds, I.S.; McNamara, D.A.; which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous Burke, J.P.; Prehn, J.H.M. Resistance CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to to Cell Death in Mucinous Colorectal cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, Cancer—A Review. Cancers 2021, 13, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for 1389. https://doi.org/10.3390/ BCL-2 proteins, including BCL-X , in preventing apoptosis in mucinous CRC has been explored to a cancers13061389 L limited extent. Additional mechanisms opposing cell death include altered death receptor expression Academic Editor: Olivier Cuvillier and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. Received: 2 February 2021 While the presence of MUC2 is associated with an immunosuppressive environment, the tumor Accepted: 10 March 2021 immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise Published: 19 March 2021 require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Keywords: mucin; colorectal; apoptosis; chemo-resistance published maps and institutional affil- iations. 1. Introduction Colorectal cancer (CRC) is a major health challenge: the global burden of CRC is Copyright: © 2021 by the authors. expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths Licensee MDPI, Basel, Switzerland. by 2030 [1]. Mucinous CRC is estimated to occur in approximately 10–15% of CRC cases This article is an open access article and is characterized by abundant extracellular mucin that comprise of at least 50% of distributed under the terms and the tumor volume [2] (Figure1). Mucinous CRCs occur more frequently in the proximal conditions of the Creative Commons colon, occur at a younger age, and have a slight female predominance compared to non- Attribution (CC BY) license (https:// mucinous CRC [3–5]. Mucinous CRCs tend to be larger than non-mucinous CRCs and creativecommons.org/licenses/by/ are more commonly diagnosed at an advanced stage [4,5]. The molecular characteristics 4.0/). Cancers 2021, 13, 1389. https://doi.org/10.3390/cancers13061389 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 15 Cancers 2021, 13, 1389 is characterized by abundant extracellular mucin that comprise of at least 50% of the tu-2 of 14 mor volume [2] (Figure 1). Mucinous CRCs occur more frequently in the proximal colon, occur at a younger age, and have a slight female predominance compared to non-mucin- ous CRC [3–5]. Mucinous CRCs tend to be larger than non-mucinous CRCs and are more of mucinouscommonly CRC suggest diagnosed that at mucinous an advanced tumors stage [4,5] develop. The molecular and progress characteristics through of mucin- different ous CRC suggest that mucinous tumors develop and progress through different molecu- molecular pathwayslar pathways compared compared with with non non-mucinous-mucinous CRCs. CRCs. Figure 1. RepresentativeFigure 1. Representative histological slides histological of: (a) mucinous slides colorectal of: (a adenocarcinoma) mucinous colorectal displaying adenocarcinomaabundant extracellular displaying mucin in abundanta 61 year old extracellularmale patient with mucin a pT4N2 in mucinous a 61 year rectal old tumor. male ( patientb) Non-mucinous with a colorectal pT4N2 mucinousadenocarcinoma rectal tumor. in a 67 year old female patient with a pT3N1 rectal tumor. H&E-stained section, 10× magnification, imaged with Leica DM 4000B microscope(b) Non-mucinous (Leica Microsystems, colorectal Mannheim, adenocarcinoma Germany). in a 67 year old female patient with a pT3N1 rectal tumor. H&E-stained section, 10× magnification, imaged with Leica DM 4000B microscope (Leica Microsystems,2. Mannheim, Molecular Characteristics Germany). of Mucinous Colorectal Cancer Sporadic CRC develops through a well-recognized pathway in approximately 85% 2. Molecularof Characteristics cases with accumulation of Mucinous of mutations Colorectal in oncogenes Cancer and tumor suppressor genes lead- ing to chromosomal instability (CIN). Mutations of the APC gene which are characteristic Sporadicof CRC chromosomal develops instability through are aless well-recognized common in mucinous pathway CRC [6] in. p53 approximately mutations are com- 85% of cases with accumulationmon in tumors ofwith mutations chromosomal in oncogenesinstability but andless common tumor suppressorin mucinous CRC genes [7]. leadingAl- to chromosomalternate instability pathways for (CIN). CRC Mutationstumorigenesis of are the describedAPC gene including which promotor are characteristic methylation of chromosomalof instability the MLH1 gene are less resulting common in sporadic in mucinous microsatellite CRC instability [6]. p53 mutations[8], and also areaberrant common in tumors withmethylation chromosomal and silencing instability of tumor but suppressor less common genes termed in mucinous epigenetic CRC instability [7]. Alternate[9]. A meta-analysis of 46 studies describing 17,746 patients by Reynolds et al. in 2019 clarified pathways formolecular CRC tumorigenesis associations of mucinous are described CRC [10]. includingMucinous CRC promotor is associated methylation positively with of the MLH1 gene resultingKRAS and in BRAF sporadic mutation, microsatellite microsatellite instabilityinstability (MSI) [8], and and the also CpG aberrant island methylator methylation and silencingphenotype of tumor (CIMP) suppressor and negatively genes termedassociated epigenetic with altered instability p53 expression [9]. [10] A. meta-analysis BRAF and of 46 studiesKRAS describing are both 17,746components patients of the RAS/MAPK by Reynolds pathway, et al. and in activation 2019 clarified of this pathway molecular promotes cell division and reduces cell apoptosis [11]. Mutations in KRAS lead to an epi- associations ofdermal mucinous growth CRCfactor [ 10receptor]. Mucinous-independent CRC disturbance is associated of the positively RAS/RAF/MAPK with KRAS path- and BRAF mutation,way, microsatellite which regulates cell instability proliferation (MSI) and andsurvival the and CpG is aisland prognostic methylator factor in CRC phenotype [12]. (CIMP) and negativelyBRAF mutatio associatedns are commonly with reported altered inp53 patientsexpression with mucinous [10]. CRCBRAF andand are associ-KRAS are both componentsated with of thean infiltrative RAS/MAPK pattern pathway,of tumor growth and [12,13] activation. In addition of this to mutations pathway in promotesKRAS cell divisionand and BRAF reduces affecting cell the apoptosis RAS/RAF/MAPK [11]. pathway, Mutations increased in KRAS mutationslead are to also an reported epidermal in the PI3K/AKT pathways in patients with mucinous CRC [12]. Aberrations in the phos- growth factorphoinositide receptor-independent 3-kinase (PI3K) disturbancesignaling pathway of the play RAS/RAF/MAPK a key role in the pathogenesis pathway, of nu- which regulates cellmerous proliferation cancers by and altering survival cellular and growth, is a metabolism, prognostic proliferation, factor in CRCand apoptosis. [12]. BRAF mutations areLeystra commonly
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