Self-renewal as a therapeutic target in human colorectal cancer

Kreso, Antonija; Galen, Peter van; Pedley, Nicholas; Lima‐Fernandes, Evelyne; Frelin, Catherine; Davis, Thomas W.; Cao, Liangxian; Baiazitov, Ramil; Du, Wu; Sydorenko, Nadiya; Moon, Young-Choon; Gibson, Lianne; Wang, Yadong; Leung, Clement H. C.; Iscove, Norman N.; Arrowsmith, C.H.; Szentgyörgyi, Eva; Gallinger, Steven; Dick, John E.; O’Brien, Catherine

doi:10.1038/nm.3418

Cited by 444 publications

(475 citation statements)

References 42 publications

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“…In cancer cell lines, we have observed that miR-215 expression can both inhibit the clonogenicity and promote the adoption of differentiated morphologies. Indeed, a recent study by Kreso et al demonstrated strikingly similar effects of small-molecule inhibition and siRNA knockdown of BMI1 in CRCs in vitro (43). Further studies of the role of miR-215 in multilineage differentiation in the normal gut and in CRC will be necessary to understand more precisely the stage at which miR-215 expression is involved in promoting differentiation in vivo.…”

Section: Discussionmentioning

confidence: 95%

The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

Jones

Hara²,

Francis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor caudal-type homeobox 1 (CDX1) is a key regulator of differentiation in the normal colon and in colorectal cancer (CRC). CDX1 activates the expression of enterocyte genes, but it is not clear how the concomitant silencing of stem cell genes is achieved. MicroRNAs (miRNAs) are important mediators of gene repression and have been implicated in tumor suppression and carcinogenesis, but the roles of miRNAs in differentiation, particularly in CRC, remain poorly understood. Here, we identified microRNA-215 (miR-215) as a direct transcriptional target of CDX1 by using highthroughput small RNA sequencing to profile miRNA expression in two pairs of CRC cell lines: CDX1-low HCT116 and HCT116 with stable CDX1 overexpression, and CDX1-high LS174T and LS174T with stable CDX1 knockdown. Validation of candidate miRNAs identified by RNA-seq in a larger cell-line panel revealed miR-215 to be most significantly correlated with CDX1 expression. Quantitative ChIP-PCR and promoter luciferase assays confirmed that CDX1 directly activates miR-215 transcription. miR-215 expression is depleted in FACS-enriched cancer stem cells compared with unsorted samples. Overexpression of miR-215 in poorly differentiated cell lines causes a decrease in clonogenicity, whereas miR-215 knockdown increases clonogenicity and impairs differentiation in CDX1-high cell lines. We identified the genome-wide targets of miR-215 and found that miR-215 mediates the repression of cell cycle and stemness genes downstream of CDX1. In particular, the miR-215 target gene BMI1 has been shown to promote stemness and self-renewal and to vary inversely with CDX1. Our work situates miR-215 as a link between CDX1 expression and BMI1 repression that governs differentiation in CRC.T he caudal-type homeobox 1 (CDX1) transcription factor controls enterocyte differentiation in the colon, where its expression is excluded from the crypt-base stem cell compartment. CDX1 is also central to the capacity of a colorectal cancer (CRC) cell line to differentiate, and it is a negative marker of CRC stem cells (1-3). In 19% of CRC cell lines assayed in a large study, CDX1 expression was completely lost due to promoter methylation and was down-regulated in a further 13% as a result of hemimethylation of the promoter (4). Comparison of CDX1 expression in colorectal adenocarcinoma versus matched normal tissue showed downregulation of CDX1 in 73% of tumors, which was also attributable to promoter methylation (5). Expression of CDX1 also correlates inversely with that of the polycomb complex protein BMI1, which is necessary for the maintenance of quiescent injury-inducible stem cells in the normal crypt and is expressed in cancer stem cells (2, 6-8). The mechanism underlying this inverse correlation has not yet been elucidated.In addition to these correlative data, CDX1 has also been shown to promote directly the expression of structural proteins important for epithelial differentiation including cytokeratin 20 (KRT20) (1), villin (VIL) (9), and FABP1 (10). Introduction...

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Section: Discussionmentioning

confidence: 95%

The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

Jones

Hara²,

Francis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…S3 C and D). Furthermore, silencing ROR1 reduced expression of Bmi-1, the polycomb ring-finger oncogene that regulates CSC self-renewal (38,39). Moreover, silencing ROR1 protein expression inhibited the expression level of EMT markers (e.g., N-cadherin and vimentin) and SNAIL1/2, master regulators of EMT (Fig.…”

Section: Silencing Expression Of Ror1 Reduces Ovarian Cancer Cell Expmentioning

confidence: 87%

Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy

Zhang

Cui

Lai

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

166

156

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Although initially responsive to chemotherapy, many patients with ovarian cancer subsequently develop relapsed and potentially fatal metastatic disease, which is thought to develop from cancer stem cells (CSCs) that are relatively resistant to conventional therapy. Here, we show that CSCs express a type I receptor tyrosine kinase-like orphan receptor (ROR1), which is expressed during embryogenesis and by many different cancers, but not normal postpartum tissues. Ovarian cancers with high levels of ROR1 had stem cell-like gene-expression signatures. Furthermore, patients with ovarian cancers with high levels of ROR1 had higher rates of relapse and a shorter median survival than patients with ovarian cancers that expressed low-to-negligible amounts of ROR1. We found that ROR1-positive (ROR1 + ) cells isolated from primary tumor-derived xenografts (PDXs) also expressed aldehyde dehydrogenase 1 (ALDH1) and had a greater capacity to form spheroids and to engraft immune-deficient mice than did ROR1-negative (ROR1 Neg ) ovarian cancer cells isolated from the same tumor population. Treatment with UC-961, an anti-ROR1 mAb, or shRNA silencing of ROR1 inhibited expression of the polycomb ring-finger oncogene, Bmi-1, and other genes associated with the epithelial-mesenchymal transition. Moreover, shRNA silencing of ROR1, depletion of ROR1 + cells, or treatment with UC-961 impaired the capacity of ovarian cancer cells to form spheroids or tumor xenografts. More importantly, treatment with anti-ROR1 affected the capacity of the xenograft to reseed a virgin mouse, indicating that targeting ROR1 may affect CSC self-renewal. Collectively, these studies indicate that ovarian CSCs express ROR1, which contributes to their capacity to form tumors, making ROR1 a potential target for the therapy of patients with ovarian cancer.ROR1 | ovarian cancer stem cell | monoclonal antibody | PDX mice model

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“…BMI-1 expression has been associated with aggressive colon cancer and poor patient outcome, and also mediates chemotherapy and radiation resistance (50). One notable study demonstrates success in specifically exploiting stem cell self-renewal as a therapeutic target, thereby providing the basis for a new therapeutic approach in CRC treatment (51). Data from this study demonstrate that tumor formation and human colorectal CSC function are dependent on the self-renewal regulator BMI-1.…”

Section: Colorectal Cscs and Targeted Therapymentioning

confidence: 75%

“…Downregulation of BMI-1 reduced human colorectal cancer growth and inhibited the ability of colorectal CSCs to self-renew, resulting in decreased tumorigenic potential. In addition, the BMI-1 inhibitor irreversibly impaired colorectal CSCs (51). Following the success of this study, future studies should focus on additional molecules and gene signatures that underlie stemness.…”

Section: Colorectal Cscs and Targeted Therapymentioning

confidence: 75%

Targeted therapy against cancer stem cells

Yang

Rycaj

2015

Oncology Letters

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Abstract. Research into cancer stem cells (CSCs), which have the ability to self-renew and give rise to more mature (differentiated) cancer cells, and which may be the cells responsible for the overall organization of a tumor, has progressed rapidly and concomitantly with recent advances in studies of normal tissue stem cells. CSCs have been reported in a wide spectrum of human tumors. Like normal tissue stem cells, CSCs similarly exhibit significant phenotypic and functional heterogeneity. The ability of CSCs to self-renew results in the immortality of malignant cells at the population level, whereas the ability of CSCs to differentiate, either fully or partially, generates the cellular hierarchy and heterogeneity commonly observed in solid tumors. CSCs also appear to have maximized their pro-survival mechanisms leading to their relative resistance to anti-cancer therapies and subsequent relapse. Studies in animal models of human cancers have also provided insight into the heterogeneity and characteristics of CSCs, helping to establish a platform for the development of novel targeted therapies against specific CSCs. In the present study, we briefly review the most recent progress in dissecting CSC heterogeneity and targeting CSCs in various human tumor systems. We also highlight a few examples of CSC-targeted drug development and clinical trials, with the ultimate aim of developing more effective therapeutic regimens that are capable of preventing tumor recurrence and metastasis. IntroductionThe etiology of cancer development and the molecular mechanisms underlying conventional therapy-resistant progression, metastasis and recurrence are poorly understood, resulting in numerous patients who still fail therapy. Cancer is recognized as a heterogeneous disease, an intrinsic attribute that contributes to therapy failure. Emerging evidence from a number of tumor systems has revealed the existence of distinct subpopulations of stem-like cancer cells, termed cancer stem cells (CSCs), that possess clonal long-term repopulation and self-renewal capacities. Theories suggest that both genetic and CSC models of cancer contribute to this tumor heterogeneity. With stemness as a guiding principle, data generated from advanced genome sequencing, epigenetics and the influences of non-tumor cell elements in the tumor microenvironment could potentially be combined in order to reveal the underlying mechanisms of tumor heterogeneity (1). As a fraction of this heterogeneous population, CSCs are inherently resistant to cytotoxic chemotherapy and radiation, and evidence has linked stemness to prognosis and therapy failure (2). This suggests that specifically identifying how CSC involvement is linked to tumor initiation, progression, metastasis and therapy resistance may lead to a more perceptive approach of developing therapeutics to target this cell population. Despite the vast complexity observed within a tumor, there are fundamental attributes of CSCs that may be exploited in drug development. A number of potential CSC therapeutic...

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Self-renewal as a therapeutic target in human colorectal cancer

Cited by 444 publications

References 42 publications

The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy

Targeted therapy against cancer stem cells

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