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Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment Against an Aggressive Tumor

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Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment Against an Aggressive Tumor International Journal of Molecular Sciences Review Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment against an Aggressive Tumor Begoña Alburquerque-González 1,2, Fernando F. López-Calderón 1,2, María Dolores López-Abellán 3, Ángel Esteban-Gil 4 , José García-Solano 1,2,5 and Pablo Conesa-Zamora 1,3,5,* 1 Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107 Murcia, Spain; [email protected] (B.A.-G.); [email protected] (F.F.L.-C.); [email protected] (J.G.-S.) 2 Department of Pathology, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202 Cartagena, Spain 3 Department of Clinical Analysis, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202 Cartagena, Spain; [email protected] 4 Biomedical Informatics & Bioinformatics Platform, Institute for Biomedical Research of Murcia (IMIB)/Foundation for Healthcare Training & Research of the Region of Murcia (FFIS), 30003 Murcia, Spain; angel.esteban@ffis.es 5 Research Group on Molecular Pathology and Pharmacogenetics, Institute for Biomedical Research of Murcia (IMIB), Calle Mezquita sn, 30202 Cartagena, Spain * Correspondence: [email protected]; Tel.: +34-968128600 (ext. 951615) Received: 7 February 2020; Accepted: 9 March 2020; Published: 14 March 2020 Abstract: Serrated adenocarcinoma (SAC) is a tumor recognized by the WHO as a histological subtype accounting for around 9% of colorectal carcinomas. Compared to conventional carcinomas, SACs are characterized by a worse prognosis, weak development of the immune response, an active invasive front and a frequent resistance to targeted therapy due to a high occurrence of KRAS or BRAF mutation. Nonetheless, several high-throughput studies have recently been carried out unveiling the biology of this cancer and identifying potential molecular targets, favoring a future histologically based treatment. This review revises the current evidence, aiming to propose potential molecular targets and specific treatments for this aggressive tumor. Keywords: colorectal cancer; serrated adenocarcinoma; angiogenesis; immune response; invasive front; molecular targets 1. Introduction Colorectal carcinoma (CRC) accounts for the third–most frequent cause of cancer death worldwide [1]. This tumor develops from precursor lesions (polyps/adenomas) following at least two pathological routes; the most common one, the adenoma–carcinoma sequence, is typically characterized by chromosomal instability and microsatellite stability leading to the development of conventional carcinoma (CC). Less is known about the serrated pathway, in which a high level of microsatellite instability (MSI-H), high frequency of BRAF mutation and the CpG island methylation phenotype (CIMP) seem to be the leading carcinogenic causes, although significant proportions of SAC are KRAS-mutated and microsatellite-stable [2,3]. These alterations contribute to the development of serrated adenocarcinoma (SAC) and the CRC showing histological and molecular features of MSI-H (hmMSI-H) [4], which are considered as endpoints of this pathway [5,6]. MSI-H is a manifestation Int. J. Mol. Sci. 2020, 21, 1991; doi:10.3390/ijms21061991 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 1991 2 of 19 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 20 of a deficiency in DNA mismatch repair mechanism which has been associated with histological medullaryfeatures including component, the presencepoor differentiation, of signet-ring “pus cells,hing” mucine, type tumor growth heterogeneity pattern, with peri- a medullaryand intra- tumoralcomponent, infiltrating poor di fflymphocytes,erentiation, “pushing”and “Crohn-l typeike” tumor inflammatory growth pattern, response peri- [7]. and SAC intra-tumoral has been recognizedinfiltrating lymphocytes,in the latest WHO and “Crohn-like”classifications inflammatory of digestive tumors response [8,9], [7]. accounts SAC has for been 7.5%–9.1% recognized of all in CRCsthe latest and WHO is diagnosed classifications based on of digestivehistological tumors criteria [8 ,9put], accounts forward forby 7.5%–9.1%Mäkinen [10,11], of all CRCsthe serrated and is appearancediagnosed based of the on epithelial histological glandular criteria putcrypts forward being by the Mäkinen most characteristic [10,11], the serrated feature appearance (Figure 1). of This the morphologicalepithelial glandular pattern crypts seems being to be the due most to characteristicapoptotic evasion feature that (Figure causes1). the This transformed morphological epithelium pattern toseems proliferate to be due laterally, to apoptotic adopting evasion a sawtooth that causes growth the transformedpattern [8,10]. epithelium In fact, apoptosis-related to proliferate laterally, genes wereadopting found a sawtooth to be enriched growth when pattern comparing [8,10]. In the fact, expr apoptosis-relatedession signature genesof SAC were with found that of to CC, be enriched and the whenimmunohistochemical comparing the expression expression signature of hippocalcin, of SAC withan anti-apoptotic that of CC, and protein, the immunohistochemical was proposed as a biomarkerexpression of of SAC hippocalcin, [12]. an anti-apoptotic protein, was proposed as a biomarker of SAC [12]. Figure 1. 1. DifferentialDifferential histological histological features features of histological of histological subtypes subtypes of colorectal of colorectal carcinoma. carcinoma. (A) Conventional(A) Conventional carcinoma carcinoma (CC) (CC)showing showing a cribriform a cribriform gland gland pattern pattern with withbasophilic basophilic cytoplasm, cytoplasm, non- stratifiednon-stratified nuclei, nuclei, lobular lobular dirty dirty necrosis necrosis (centre) (centre) and andlymphocytic lymphocytic infiltrates infiltrates (upper-left (upper-left corner). corner). (B) Serrated(B) Serrated adenocarcinoma adenocarcinoma (SAC) (SAC) with with typical typical vesicular vesicular stratified stratified nuclei, nuclei, eosinophilic eosinophilic cytoplasm cytoplasm and serratedand serrated lumen lumen (left (leftgland) gland) with withweak weak lymphocyti lymphocyticc infiltration, infiltration, tumor tumor budding budding (black (black arrows) arrows) and desmoplasticand desmoplastic stroma. stroma. (C) Colorectal (C) Colorectal carcinoma carcinoma (CRC) with (CRC) histological with histological and molecular and features molecular of microsatellitefeatures of microsatellite instability (hmMSI-H) instability (hmMSI-H)characterize characterizedd by a medullar by a“solid” medullar pattern “solid” and pattern abundant and abundant intraepithelial tumor-infiltrating lymphocytes (black arrows) 20 original magnification. intraepithelial tumor-infiltrating lymphocytes (black arrows) 20× original× magnification. (Source: Authors).(Source: Authors). SAC develops from serrated adenomas through a fast process. Therefore, it is not unexpected that SAC develops from serrated adenomas through a fast process. Therefore, it is not unexpected SACs are frequently found as “interval” CRCs and are related with synchronous and metachronous that SACs are frequently found as “interval” CRCs and are related with synchronous and advanced colorectal tumors [13]. In addition to this higher abundance of synchronous carcinoma metachronous advanced colorectal tumors [13]. In addition to this higher abundance of synchronous compared to CC, distant polyps present in surgical resections containing SAC frequently show carcinoma compared to CC, distant polyps present in surgical resections containing SAC frequently showserrated serrated morphology, morphology, thus suggesting thus suggesting a bystander a byst eanderffect or effect individual or individual predisposition predisposition for serrated for serratedcarcinogenesis carcinogenesis [11]. At this [11]. point At this it, is point noteworthy it, is noteworthy that smoking that andsmoking alcohol and abuse alcohol have abuse been have associated been withassociated the development with the development of the serrated of the carcinogenesis serrated carcinogenesis pathway [14 pathway–16], as well[14–16] as, theas presencewell as the of Fusobacterium nucleatum presence of Fusobacteriumin nucleatum the patient’s in the feces patient’s [17]. feces [17]. Not surprisingly, SAC has a worse prognosis than CC [[11],11], and in-depth studies have revealed that, comparedcompared to to CC, CC, SAC SAC shows shows a more a more prominent prominen invasivet invasive front, whichfront, iswhich characterized is characterized by abundant by abundanthistologically histologically adverse prognostic adverse factors prognostic such as tumorfactors budding, such as cytoplasmic tumor budding, pseudofragments cytoplasmic and pseudofragmentsan invasive tumor and infiltrating an invasive pattern tumor [18]. infiltrating Consequently, pattern the [18]. loss ofConsequently, E-cadherin expressionthe loss of and E- cadherinthe increase expression in mesenchymal and the increase markers in are mesenchymal more evident markers in SAC are than more in CCevident [19]. in These SAC histologicalthan in CC [19].and immunohistochemicalThese histological and manifestations immunohistochemical of the invasive manifestations activity ofof SACthe invasive tumor cells activity were of further SAC tumorconfirmed cells by were analyzing further the confirmed molecular by signatures analyzing of the SAC molecular compared signatures to CC, where of SAC functions compared associated to CC, withwhere
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