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

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 attributed initially to cause other than cancer.

Dormant CSCs (micrometastases) cannot be detected by current imaging examination methods and are overlooked.

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 becomes apparent very quickly.

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

A second pattern involves patients whose tumors exhibit primary resistance. These patients never experience tumor shrinkage even with the initial treatment option.

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 metastases in the same organ can have different somatic profiles.

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 potential, and metastatic capacity [56]. Furthermore, the drug-resistant cells exhibited other CSC properties, including higher sphere-forming capacity and expression of the CSC markers Oct4, CD133, and CD44 [56]. The increase in CSC potential was accompanied by downregulation of the AKT signaling pathway and upregulation of the STAT3 pathway. The STAT3 pathway was activated by Notch-dependent autocrine secretion of interleukin 6 [56].

These are real problems in the clinic, which are difficult to control. In solving this problem, it is necessary to penetrate into the cellular or molecular basis of gastric cancer and speculate whether different clinical outcomes reflect different CSC populations or molecular characteristics.

Gastric cancer is a heterogeneous disease with diverse molecular characteristics. Multiple experimental and clinical investigations have implicated a wide range of germ line and somatic alterations that drive tumor progression [57]. Recently, the Cancer Genome Atlas Research Network analyzed nearly 300 samples of previously untreated gastric and gastroesophageal cancer and grouped them into four major molecular subtypes [58]:

