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Topic: Reviews of Recent Advances in Research and Treatment for
Gastroenterological Malignancies

Molecular insights into colorectal cancer stem cell regulation by
environmental factors

Daisuke Izumi , Takatsugu Ishimoto , Yasuo Sakamoto , Yuji Miyamoto , Hideo Baba 1
1
1
1
1,2
1 Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
2 Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School Singapore, 169857 Singapore.
Correspondence to: Dr. Takatsugu Ishimoto, Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road,
169857 Singapore. E-mail: taka1516@kumamoto-u.ac.jp
ABSTRACT
Colorectal cancer remains a signifi cant cause of cancer-related mortality worldwide, mainly because of tumor relapse and
metastases. Cancer stem cells (CSCs) are considered to be the main cause of resistance to chemotherapeutic agents, as well as
being responsible for distant metastases. Although CSCs themselves possess innate abilities for self-renewal and differentiation, the
environment surrounding CSCs provides oxygen, nutrients and secreted factors, and also supports angiogenesis, thus it's responsible
for maintaining their CSC properties. Furthermore, extensive investigations have revealed that obesity, accompanied by excess
visceral adipose tissue, induces chronic infl ammation, and is linked to the risk and progression of several gastrointestinal cancers,
through modulating the capacities of the CSCs. This review presents the evidence linking colorectal CSCs and their environment
and summarizes our current understanding of the molecular mechanisms underlying this relationship.
Key words: Cancer stem cells markers, colorectal cancer stem cell, nutrient, obesity, tumor microenvironment

Introduction initiation and clonal long-term repopulation. [17,18]
The discovery of colorectal CSCs highlighted the
Colorectal cancer (CRC) is the fourth-leading cause of existence of intratumoral heterogeneity, revealing
[1]
cancer-related deaths worldwide. Although the incidence the presence of tumor cells expressing markers
of CRC has started to decline in developed countries, characteristic of immature cells and with increased
[2]
it continues to increase in developing countries. abilities to resist chemotherapy and to seed secondary
Environmental factors, including chronic infl ammation, tumors. [19-21] CSCs were initially considered to be
obesity, metabolism and nutrition, have become a cell population with well-defined phenotypic and
recognized as major contributors to the development molecular features. However, emerging evidence has
of CRC. [3-6] Dietary fat intake and obesity have been revealed that certain cancer cells exhibit plasticity,
shown to be signifi cantly involved in CRC progression and can change reversibly from stem to non-stem
through an increased risk of gene mutation, epigenomic cells under the regulation of genetic, epigenetic and
alterations, and effects on the equilibrium of various microenvironmental factors. [22-25] In this review, we
adipokines. [7-11] Chronic infl ammation is also considered focused on accumulating new evidence indicating
[6]
to be a risk factor for CRC, and infl ammatory mediators that microenvironmental factors maintained colorectal
and substances such as interleukin (IL)-6, tumor necrosis CSC properties responsible for promoting tumor
factor-α (TNF-α), and reactive oxygen species have been development and metastasis.
shown to affect CRC development. [12-15] The clearest link
between chronic infl ammation and CRC is seen in patients Markers for Colorectal CSCs
with infl ammatory bowel disease, which has been reported
to promote tumorigenesis by altering the microbial CSCs have been isolated from cancer tissues using
composition in the gut and supporting the expansion of fl ow cytometry with specifi c surface markers.
microorganisms with genotoxic capabilities. [16] Several molecules have been proposed as colorectal
Cancer stem cells (CSCs) are tumor cells that
possess capabilities for self-renewal, clonal tumor This is an open access article distributed under the terms of the Creative
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How to cite this article: Izumi D, Ishimoto T, Sakamoto Y, Miyamoto Y,
Bab H. Molecular insights into colorectal cancer stem cell regulation
DOI: by environmental factors. J Cancer Metastasis Treat 2015;1:156-62.
10.4103/2394-4722.165532
Received: 05-07-2015; Accepted: 21-07-2015.
156 © 2015 Journal of Cancer Metastasis and Treatment ¦ Published by Wolters Kluwer - Medknow