Preprint Article Version 1 This version is not peer-reviewed

Expression of Intestinal Stem Cell and Cancer Stem Cell Markers in Submucosal Invasion and Its Prognostic Significance in Gastric Cancers

Version 1 : Received: 20 July 2020 / Approved: 21 July 2020 / Online: 21 July 2020 (12:34:02 CEST)

How to cite: Kim, H.S.; Song, H.J.; Jeong, I.H.; Jang, B.G. Expression of Intestinal Stem Cell and Cancer Stem Cell Markers in Submucosal Invasion and Its Prognostic Significance in Gastric Cancers. Preprints 2020, 2020070484 (doi: 10.20944/preprints202007.0484.v1). Kim, H.S.; Song, H.J.; Jeong, I.H.; Jang, B.G. Expression of Intestinal Stem Cell and Cancer Stem Cell Markers in Submucosal Invasion and Its Prognostic Significance in Gastric Cancers. Preprints 2020, 2020070484 (doi: 10.20944/preprints202007.0484.v1).

Abstract

Submucosal invasion is a critical step in gastric cancer (GC) progression, which greatly enhances metastasis risk. Cancer stem cells are responsible for invasion, metastasis, and tumor growth. To identify stem cell-related markers associated with submucosal invasion in GCs, we investigated the expression of candidate cancer stem cell (CSC) markers (CD133, CD44, and ALDH1A) and intestinal stem cell (ISC) markers (EPHB2, OLFM4, and LGR5) in early GCs with submucosal invasion. Remarkably, expression of all ISC markers and CD133 was frequently confined to the basal area of the lamina propria (basal pattern) in mucosal cancer. The proportion of stem cell marker-positive cells substantially increased during submucosal invasion. Given that ISC markers are restricted to the crypt base of the normal intestinal mucosa, these findings suggest that many early GCs may retain hierarchical characteristics. CD44 expression showed a focal pattern, ALDH1A was predominantly expressed diffusely, and there was no expansion of CD44 or ALDH1A expression in the submucosal cancer cells. RSPO2 from muscularis mucosa seem to be partly responsible for the increased expression of ISC markers in GC cells at the basal areas. We also found that ISC markers were correlated with CDX2 expression in GCs, indicating that ISC markers are involved in the intestinal differentiation in GCs. Interestingly, ISC markers (EPHB2 and OLFM4) and CD133 showed a positive impact on clinical outcomes. In particular, the prognostic value of EPHB2 was significant for intestinal-type GCs in a multivariate analysis. In summary, ISC markers and CD133 showed a basal distribution pattern along with enhanced expression in submucosal invading cells in early GCs. EPHB2 was an independent prognostic marker in intestinal-type GCs.

Subject Areas

Gastric cancer; Submucosal invasion; Intestinal stem cell; Cancer stem cell; Prognosis

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