Page 38 - Read Online

Colorectal CSCs Niche in the Tumor Several studies have reported that CSCs reside in
Microenvironment perivascular niches in certain types of cancer. [62-64]
Endothelial-cell-derived, soluble Jagged-1 led to Notch
Tissue stem cells reside in their surrounding activation in colorectal CSC cells in a paracrine manner,
microenvironment, known as the stem cell niche, and play thus promoting the CSC phenotype. [65]
an essential role in maintaining tissue homeostasis through
their abilities of self-renewal and differentiation. [46,47] Hypoxia is known to play pivotal roles in cell survival,
Lgr5+ stem cells in the intestinal crypts are interspersed angiogenesis, tumor invasion and metastasis, and is
among terminally differentiated Paneth cells, which act as involved in the maintenance of self-renewal and the
guardians of the stem cells by providing essential niche undifferentiated state of CSCs in various types of
[48]
signals. The tumor microenvironment surrounding tumors. [66-68] According to a study of colorectal cell
cancer cells contains multiple cell types including immune line-derived CSCs, hypoxia maintained their stem-like
cells, endothelial cells, and fi broblasts, in addition to the phenotype and prevented differentiation of enterocytes
extracellular matrix. Recent evidence suggests that cancer and goblet cells by regulating CDX1 and Notch1. [69]
cells interact with their microenvironment and each other
by secreting growth factors, cytokines, and proteases. Obesity, Nutrients, and Colorectal CSCs
Furthermore, the properties of the CSCs depend on Properties
the CSC niche, which regulates their proliferation and Obesity and visceral adiposity are closely related to
differentiation, as well as those of the tissue stem cells. disorders such as diabetes, cardiovascular disease, and
Mesenchymal stem cells (MSCs) have been shown to be increased risk of various cancers, including CRC. [4,70,71]
recruited into the tumor stroma, and to enhance tumor Although a meta-analysis showed that an increase in the
growth and metastasis in CRC. MSCs are considered body mass index in men was associated with a relative
[49]
[72]
as potential precursors of carcinoma-associated CRC risk of 1.24, the relationship between increased
fibroblasts (CAFs, also known as tumor-associated body mass index and CRC risk in women is inconsistent.
fi broblasts), which play a key role in tumor progression It is possible that the insulin and the insulin-like growth
in various types of cancer, including CRC. [50-52] factor-1 axis may play different roles in colorectal
Carcinoma-cell-derived IL-1 was shown to induce carcinogenesis in men and women. [4,73]
prostaglandin E2 (PGE2) secretion by MSCs, and the Visceral obesity is associated with increased infi ltration of
resulting PGE2 then acted in an autocrine manner infl ammatory cells such as macrophages and T-cells into the
with ongoing paracrine IL-1 signaling to induce adipose tissue, together with low-grade infl ammation. [74-77]
expression of cytokines by the MSC, thus creating a Adipose tissues produce various growth factors, hormones,
CSC niche. A recent study demonstrated that CRC and cytokines known as adipocytokines, including leptin,
[53]
cells can induce adjoining bone-marrow-derived MSCs resistin, visfatin, adiponectin, and numerous infl ammatory
to exhibit the typical characteristics of CAFs in vitro, mediators such as TNF-α, IL-6, IL-8, IL-10, and IL-1
and activated Notch signaling mediates transformation receptor agonists. These adipose-derived factors have
of bone-marrow-derived MSCs to CAFs through the demonstrated an intimate involvement in increased
downstream TGF-β/Smad signaling pathway. Cytokines risk of CRC. In addition to adipocytokine-mediated
[54]
[4]
secreted by CAFs, including hepatocyte growth factor, infl ammation, dyslipidemia, insulin resistance, and
osteopontin, and stromal-derived factor 1α, increase activation of the renin-angiotensin system may also
CD44v6 expression in colorectal CRCs, which in turn contribute to CRC development. [78]
promote migration and metastasis. Another study
[55]
demonstrated that CSCs were resistant to conventional Colorectal CSC clones have been reported to express
chemotherapy and that chemoresistance was also leptin receptors and to respond to leptin by cell
increased by CAFs. In this study, chemotherapy-treated proliferation, activation of the ERK1/2 and PI3K/AKT
human CAFs promoted CSC self-renewal and in vivo signaling pathways, enhanced growth in soft agar, and
tumor growth associated with secretion of cytokines and improved sphere formation associated with E-cadherin
chemokines, including IL-17A. [56] overexpression. Moreover, leptin counteracted the
cytotoxic effects of 5-fl uorouracil. Other authors
[79]
The Wnt/β-catenin signaling pathway has been shown reported that leptin acted as a growth factor for
to play critical roles during the transition from normal carcinogen-induced colorectal tumors in a mouse
colorectal mucosa to adenocarcinoma. [57-59] The tumor model of obesity. They also showed that leptin receptor
microenvironment may play a central role in malignant expression levels were markedly increased in colorectal
transformation by locally modifying β-catenin activity tumors compared with normal epithelium, in association
in tumor cells, thus contributing to tumor growth with activation of Wnt signaling. [80]
and cancer stemness. Likewise, myofi broblast-secreted
[60]
factors, especially hepatocyte growth factor, activated Chronic infl ammation is considered to be a risk factor for
Wnt signaling and restored the CSC phenotype in more CRC, and an obvious association has been demonstrated
differentiated tumor cells both in vitro and in vivo. [61] between the incidence of CRC and infl ammatory

158 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦