**3.9. Identifying CSCs**

of CSCs. However, the direct relationship between CSCs and EMT in terms of molecular mecha-

Gastric cancer is usually diagnosed at later stages. This may be because patients often do not exhibit symptoms until their disease has progressed, or their symptoms have been vague and

Dormant CSCs (micrometastases) cannot be detected by current imaging examination methods

When the primary tumor is treated, whether with preoperative chemotherapy and/or chemoradiation followed by surgery, we observe several phenomena. The primary tumor is often resistant to therapy. We know from our experience that the more resistant the primary tumor is, the more metastatic potential it has. In other words, this aggressive biology, which is probably related to the number of CSCs (and evolved species of CSCs) present in the primary tumor or volume of the tumor, dictates metastatic potential. In addition, although it may appear that local treatment has been successful, highly resistant metastatic disease often

We distinguish three patterns of response and resistance observed in patients with advanced and metastatic gastric cancer following first-line therapy (docetaxel, cisplatin, and 5-FU).

A first pattern involves patients with gastric cancer, where there is almost a 50% chance they will experience some reduction in tumor volume and improvement in their symptoms for a short time, but, after a few months, the cancer starts to grow. Second-line therapy produces less reduction in tumor volume and for a shorter duration response. Between these patients, it can be seen that the

A second pattern involves patients whose tumors exhibit primary resistance. These patients

A third resistance pattern is one in which the patient has a mixed treatment response. Metastatic lesions in the liver, for example, will become smaller, while those in abdominal lymph nodes increase in size. This phenomenon is intrapatient tumor heterogeneity. Not only can tumors in different organs exhibit different molecular characteristics, but multiple metas-

While an anti-HER2–targeted therapy is showing efficacy, only about 20% of gastric cancers overexpress HER2 [56]. In a review of first-line therapy in patients with metastatic disease, the inclusion of an anti-HER2–targeted agent provided a modest increase in survival to slightly more than 1 year [56]. Patients receiving anti-HER2 therapy develop resistance immediately after treatment. Recently, the mechanism of acquired resistance to the anti-HER2–targeted agent trastuzumab in gastric cancer has been explored. Treatment of gastric cancer cells for 20 weeks with trastuzumab resulted in epithelial-mesenchymal transition (EMT) induction in drug-resistant cells. This EMT induction was characterized by loss of E-cadherin and ZO1, as well as overexpression of claudin-1, vimentin, β-catenin, ZEB1, Slug, and Snail 22. These drug-resistant cells also exhibited an aggressive tumor phenotype, including higher motility, invasion potential, tumor formation

CSCs population is enriched by cancer treatments, making the tumor more resistant.

never experience tumor shrinkage even with the initial treatment option.

tases in the same organ can have different somatic profiles.

**3.8. The cancer stem cells phenomenon and the clinical course of the disease**

nisms remains to be elucidated.

becomes apparent very quickly.

and are overlooked.

254 Gastric Cancer

attributed initially to cause other than cancer.

Cancer stem cells in solid tumors were first reported in breast cancer (CD44<sup>+</sup> CD24<sup>−</sup> /low fraction) [60].

The first report of gastrointestinal CSCs was in the CD133<sup>+</sup> CD44+ ALDH1+ fraction of colorectal cancer [61].

Subsequently, gastrointestinal CSCs have been detected in cancers of esophagus, stomach, liver, and pancreas [62].

To distinguish CSCs from other cancer cells, researchers have developed profiles of unique cellular markers. These profiles allow detection of CSCs within a tumor and enable the separation of CSCs from nonstem cancer cells for *research purposes*.

Markers and characteristics of the cancer stem cells:


The existence of CSCs in gastric cancer was first revealed by analyzing a panel of gastric cancer cell lines [64, 65]. Cancer stem cells from either gastric cancer cell lines or resected tumors were isolated using cell surface markers, such as CD44 and epithelial cell adhesion molecule (EpCAM) [65]. Moreover, gastric CSCs can even be isolated from the peripheral blood of gastric cancer patients using CD44 and CD54.

Leucine-rich repeat containing G protein-coupled receptor-5 (Lgr5) is a gastric CSC marker and Lgr5+ stem cells in the stomach could be the origin of gastric CSCs [66]. Patients with gastric cancer containing Lgr5+ cells have a short median survival [66].

Stem cells that express villin exist in the pyloric gland and villin + gastric stem cells might be converted to gastric cancer cells [66]. Kruppel-like factor-4 (KLF4) might play a critical role in gastric cancer initiation and progression in villin + gastric stem cells [66].

In addition, ALDH1, CD90, CD71, and CD133 could be candidate markers of gastric CSCs. MicroRNAs might regulate the properties of gastric CSCs by inducing epithelial-mesenchymal transition [67].

It must be noted, however, that no set of markers are exclusive to CSCs, and also that CSC phenotypes vary over time and between individual patients' tumors of the same subtype. These facts have caused researchers to speculate whether different clinical outcomes reflect different CSC populations [63].

#### **3.10. Treatment of the cancer stem cells**

Multiple research findings indicate that conventional therapies, which target the rapidly dividing cells in tumors, have limited efficacy or even adverse effects on CSCs [30] and lead to treatment failure, chemoresistance, and recurrence.

Consequently, two types of cancer therapies targeting CSCs have been investigated: first, to induce and/or maintain dormancy of tumor cells, and second, to induce cell death in residual dormant cancer cells by targeting their markers. Consequently, gastric cancer therapies targeting CSCs have been investigated (**Table 3**) [70].

Gastric Cancer with Liver Metastasis (GCLM) and the Importance of Dormant Cancer Stem Cells http://dx.doi.org/10.5772/intechopen.69829 257


JAK, Janus-activated kinase; VEGF-R, VEGF receptor; EZH2, enhancer of zeste homolog 2; ABC, ATP-binding cassette.

**Table 3.** Target molecules and pathways for gastric cancer stem cells.

#### **3.11. The risks of anticancer stem cells (CSCs) therapy**

