Abstract
The cancer stem cell model is considered as a putative cause of resistance to chemotherapy and disease recurrence in malignant tumors. In this study, we tested the hypothesis that the response to neoadjuvant/perioperative chemotherapy correlates with the expression of four different putative cancer stem cell markers of gastric cancer (GC), i.e., LGR5, FZD7, TROY, and MIST1. The expression of LGR5, FZD7, TROY, and MIST1 was assessed by immunohistochemistry in 119 perioperatively treated GCs including pretherapeutic biopsies, resected primary GCs, and corresponding nodal and distant metastases. All four markers were detected in our cohort with variable prevalence and histoanatomical distributions. Few tumor cells expressed TROY. LGR5, FZD7, and MIST1 were coexpressed in 41.2% and completely absent in 6.2%. The prevalence of LGR5- and FZD7-positive GCs was higher and of TROY-positive GCs lower in perioperatively treated GCs compared with treatment-naïve tumors. LGR5, FZD7, and MIST1 in the primary tumors correlated significantly with their expression in the corresponding lymph node metastasis. An increased expression of LGR5 in primary GC correlated significantly with tumor regression. The expression of MIST1 in lymph node metastases correlated significantly with the number of lymph node metastases as well as overall and tumor-specific survival. FZD7 did not correlate with any clinicopathological patient characteristic. Our study on clinical patient samples shows that GCs may coexpress independently different stem cell markers; that neoadjuvant/perioperative treatment of GC significantly impacts on the expression of stem cell markers, which cannot be predicted by the analysis of pretherapeutic biopsies; and that their expression and tumor biological effect are heterogeneous and have to be viewed as a function of histoanatomical distribution.
Highlights
Gastric cancer (GC) is a leading cause of cancer death worldwide [1]
We tested the hypothesis that the response to neoadjuvant/perioperative chemotherapy correlates with the expression of four different cancer stem cells (CSC) markers of GC, i.e., LGR5, FZD7, TROY, and MIST1 by using clinical samples
Thirteen patients (10.9%) showed complete tumor regression of the primary tumor (Becker regression score 1a), of which three still had viable tumor cells in lymph node metastases suitable for histological classification. 25 cases (21%) contained less than 10% of vital tumor residuals in the primary tumor tissue (Becker regression score 1b). 19 (16%) contained 10-50% of vital tumor residuals (Becker regression score 2) and 62 (52.1%) showed more than 50% of vital tumor residuals (Becker regression score 3). 25 patients (21%) had a diffuse, 52 (43.7%) an intestinal, 18 (15.1%) a mixed, and 14 (11.8%) an unclassifiable type of GC according to Laurén [49]
Summary
Gastric cancer (GC) is a leading cause of cancer death worldwide [1]. In Western countries, GC is often diagnosed at an advanced stage, leading to an overall poor prognosis [2]. Several studies have shown that patients with limited metastatic disease benefit from neoadjuvant/perioperative chemotherapy [3,4,5]. The tumor stem cell hypothesis assumes that chemotherapy leads to a selective survival of resistant cancer stem cells (CSC), which are protected by different mechanisms from the effects of chemotherapy [7]. CSCs are able to initiate tumor regrowth leading to tumor recurrence [7]. The resistance of CSCs to conventional chemotherapeutic agents has been demonstrated in a large number of studies [8,9,10], raising hopes that CSCs may serve as predictive or prognostic markers of therapeutic efficacy. Evidence in clinical samples is scarce often due to the lack of appropriate biomarkers to screen for CSCs in tissue samples.
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