OLFM4 Is a Robust Marker for Stem Cells in Human Intestine and Marks a Subset of Colorectal Cancer Cells

Flier, Laurens G. van der; Haegebarth, Andrea; Stange, Daniel E.; Wetering, Marc van de; Clevers, Hans

doi:10.1053/j.gastro.2009.05.035

Cited by 463 publications

(380 citation statements)

References 22 publications

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“…Similarly, PHLDA1 showed more restricted expression as compared with the published in situ hybridization results for OLFM4, a suggested marker of ISCs in the human (12). Although both PHLDA1 and BMI1 protein were expressed in a proportion of þ4 cells, our data did not conclusively demonstrate an overlap between these 2 populations.…”

Section: Discussioncontrasting

confidence: 51%

“…Conflicting data exist on BMI1 mRNA and protein expression in human small and large intestine (9)(10)(11), and systematic assessment of LGR5, ASCL2, and OLFM4 is hindered by a lack of appropriate antibodies and has been limited to surrogate in situ hybridization studies. OLFM4 is perhaps the best studied candidate in humans, showing mRNA expression at the crypt base throughout the intestinal tract (12). OLFM4 appears to be highly expressed in a subset of colorectal carcinoma cells, although data is limited to a small number of tumors (12).…”

Section: Introductionmentioning

confidence: 99%

“…OLFM4 is perhaps the best studied candidate in humans, showing mRNA expression at the crypt base throughout the intestinal tract (12). OLFM4 appears to be highly expressed in a subset of colorectal carcinoma cells, although data is limited to a small number of tumors (12).…”

Section: Introductionmentioning

confidence: 99%

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PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

et al. 2011

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Studies employing mouse models have identified crypt base and position þ4 cells as strong candidates for intestinal epithelial stem cells. Equivalent cell populations are thought to exist in the human intestine; however robust and specific protein markers are lacking. Here, we show that in the human small and large intestine, PHLDA1 is expressed in discrete crypt base and some position þ4 cells. In small adenomas, PHLDA1 was expressed in a subset of undifferentiated and predominantly Ki-67-negative neoplastic cells, suggesting that a basic hierarchy of differentiation is retained in early tumorigenesis. In large adenomas, carcinomas, and metastases PHLDA1 expression became widespread, with increased expression and nuclear localization at invasive margins. siRNA-mediated suppression of PHLDA1 in colon cancer cells inhibited migration and anchorage-independent growth in vitro and tumor growth in vivo. The integrins ITGA2 and ITGA6 were downregulated in response to PHLDA1 suppression, and accordingly cell adhesion to laminin and collagen was significantly reduced. We conclude that PHLDA1 is a putative epithelial stem cell marker in the human small and large intestine and contributes to migration and proliferation in colon cancer cells. Cancer Res; 71(10);

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Section: Discussioncontrasting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

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PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

et al. 2011

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“…S7). The top candidate from this analysis, olfactomedin 4 (OLFM4), reported to be an intestinal stem cell marker, 25 was on average >6-fold lower expressed in carcinomas with chr16p-loss than without (p ¼ 7.34 Â 10 À4 ). However, when corrected for multiple testing (Benjamini-Hochberg) significance was not reached for this or any other gene.…”

Section: Chr16p-loss and Transcriptional Alterationsmentioning

confidence: 99%

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Andersen

Lamy

Thorsen

et al. 2011

Intl Journal of Cancer

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Genomic alterations play important roles in colorectal cancer (CRC) carcinogenesis. Here, we aimed to identify and characterize recurrent copy-number alterations (CNAs) associated with clinical outcome of CRC by the use of single nucleotide polymorphism arrays, genomic quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Colorectal neoplasia specimens and paired germline samples from 144 patients (40 adenomas and 104 carcinomas) as well as 40 CRC cell lines were investigated. This large dataset revealed frequent loss, including homozygous loss, at chr16p13.2 (from 5.9 to 7.42Mb). The loss was observed in 30% of adenomas and even more frequently in carcinomas, 56%, indicating that the loss define a subset of adenomas with a propensity for invasion. Consistent with this, the loss occurred twice as frequent in villous (40%) as in tubular adenomas (20%). The loss occurred independently of microsatellite stability and could be validated by qPCR in an independent sample cohort (n 5 71). In Stage II/III, microsatellite stable (MSS) CRC it was associated with poor recurrence free survival (hazard ratio 2.4; p 5 0.02; Multivariate Cox regression analysis). No transcriptional consequences of the losses were observed, and the only gene, A2BP1, located in the region showed no mutations. Correlation with other CNAs was established for chr3p22 in carcinomas and chr20p (inverse) in adenomas. FISH documented the chr16p13.2 region to be involved in complex structural rearrangements that included translocation to chr3p22 in some cases. The findings indicate that structural rearrangements involving chr16p13.2 are very frequent in colorectal neoplasia, often lead to homozygous deletion, and are associated with poor clinical outcome.Despite major efforts over the recent years toward improving the survival outcome of patients with colorectal cancer (CRC), the disease remains a major health burden with over one million cases worldwide and a disease-specific mortality of $33% in the developed world. 1 Currently, the gold standard for prognostication is clinicopathological staging, based on the Tumor, Node, Metastasis (TNM) classifcation. However. Although CRC is often diagnosed at a stage where complete resection of the primary cancer (Stages I-III) is possible, 40-50% of patients who undergo potentially curative surgery alone relapse and die of metastatic disease. 2 Although most patients with Stage III (lymph-node positive) cancer receive adjuvant treatment, it is offered to only a subset of Stage II (localized disease) patients presenting with specific high-risk clinical features, including tumor perforation or invasion of adjacent organs. 3 This approach is clearly suboptimal, resulting in undertreatment of $20% of Stage II patients who will recur. Similarly, current adjuvant treatment is clearly ineffective in many Stage III patients, with a recurrence rate of $40% 4,5 highlighting the need for treatment with more aggressive or newly emerging targeted therapies, e.g., inhibitors of epidermal growth factor recepto...

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“…Rather than relying on putative marker expression, Buczacki et al focused on cells with functional label retention properties and in a series of elegant experiments, demonstrated that these cells are committed secretory cell precursors that retain the capability of returning to stem cell function in the event of intestinal damage and regeneration 18. Numerous other markers have been used to identify populations that are enriched for cells capable of lineage tracing in the intestine including Tert , Hopx , Lrig1 , Sox9 , Ascl2 , Olfm4 , Prom1 , and Rnf43 15, 19, 20, 21, 22.…”

Section: Stem Cell Identificationmentioning

confidence: 99%

Microenvironmental control of stem cell fate in intestinal homeostasis and disease

Biswas

Belnoue-Davis

Irshad

et al. 2015

The Journal of Pathology

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The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt–luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies. © 2015 Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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OLFM4 Is a Robust Marker for Stem Cells in Human Intestine and Marks a Subset of Colorectal Cancer Cells

Cited by 463 publications

References 22 publications

PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Microenvironmental control of stem cell fate in intestinal homeostasis and disease

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