• 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • Herboxidiene br Parts of this study have been presented at t


    ★ Parts of this study have been presented at the United States and Canadian Academy of Pathology Annual Meeting in March 2018. Corresponding author.
    E-mail address: [email protected] (M. J. Cecchini).
    CDX2 and Muc2 in stage II colon cancer 71
    1. Introduction
    Treatment of colorectal cancer (CRC) is largely surgical with resection of the primary tumor and treatment with adju-vant chemotherapy in specific cases, such as stage III cancers where there is a clear survival benefit for the use of adjuvant chemotherapy [1]. However, in patients with stage II cancer, multiple clinical studies have failed to identify a significant benefit for the use of adjuvant therapy [2,3]. Most patients with stage II disease have a good prognosis with 5-year survival on the order of 75% [3]. There is a need to identify stage II pa-tients who are at higher risk of disease recurrence, as these pa-tients would likely benefit from adjuvant therapies. Classic high-risk features (such as T4 disease and lymphovascular or venous invasion) have failed to identify those patients who would benefit from adjuvant therapy [2]. Nevertheless, adju-vant therapy is still commonly used in clinical practice for stage II patients with perceived high risk [4].
    Recently, it was demonstrated that tumors with gene ex-pression signatures similar to undifferentiated colonic stem Herboxidiene were more aggressive, and this could be used to predict relapse [5]. It was subsequently shown, using a tissue microar-ray–based experiment, that this could be simplified and loss of CDX2 alone could be used as a marker for the undifferentiated colonic stem cell gene signature [6]. In this study of stage II CRC, 9% of cases had loss of CDX2 expression, and this was associated with a significantly reduced disease-free sur-vival [6]. This difference in outcome was not seen in CDX2-negative stage II patients who received chemotherapy [6], leading to the conclusion that loss of CDX2 could be used to predict patients who would respond to chemotherapy. CDX2 status was proposed as both a prognostic and predictive bio-marker in CRC to identify early-stage high-risk colon cancer and predict those who would respond to chemotherapy. Publi-cation of this role of CDX2 [7-11] was initially met with hope as a novel means to guide treatment decisions in CRC patients.
    However, other groups reported that the findings could not be independently confirmed in other gene expression datasets of colon cancer [12]. Other studies have had variable findings; one showed that loss of CDX2 in metastatic disease was a neg-ative prognostic indicator [13], whereas another study of pa-tients with mostly advanced stage III and IV disease who received chemotherapy found that CDX2 was not an indepen-dent prognostic biomarker in CRC [14]. A gene expression study of a mixture of stage II and III cases found that CDX2 loss predicted a negative outcome only in tumors with the CMS4 molecular phenotype, a mesenchymal/stem cell pheno-type [15]. Another group has generated a large tissue microar-ray of 613 colon cancers with multiple tumor areas arrayed to better appreciate intratumor heterogeneity but have yet to re-port outcome data from their study [16]. No study reported to date has been able to confirm the findings using whole-slide immunohistochemistry for CDX2 in stage II colon cancer.
    CDX2 is a member of the Caudal-type homeobox (CDX) genes that are closely related to the Hox cluster and have a role in the patterning of embryos [17]. CDX2 is critical for 
    intestinal differentiation; mice lacking CDX2 have replace-ment of the intestinal mucosa with gastric and esophageal type tissue [18]. Loss of CDX2 has been associated with distinct pathways of CRC tumorigenesis, for example, CpG island methylator phenotype (CIMP) [19-21]. There is a less clear as-sociation between CDX2 and microsatellite instability (MSI); although a number of studies have identified an association be-tween CDX2 status and MSI [20-23], others have failed to identify that connection [24-26].
    Other markers comprising the gene expression signatures for colonic differentiation included Muc2, CDX1, GPX2, and villin. CDX1 is a related transcriptional factor to CDX2 and also has a critical role in specifying intestinal differentia-tion [27] and its loss functions synergistically with loss of CDX2 to promote tumorigenesis in experimental models of CRC [28]. GPX2 has an important role in reducing H2O2 and has been shown to promote tumor cell differentiation [29]. Villin is an actin-binding protein within the brush border of enterocytes. Muc2 is a member of the mucin family of epi-thelial glycoproteins that are expressed in colonic epithelium and colorectal tumors [30,31]; loss of expression has been as-sociated with adverse prognostic features in colon cancer [32].