CD49fhigh Cells Retain Sphere-Forming and Tumor-Initiating Activities in Human Gastric Tumors

Abstract

Identification of gastric tumor-initiating cells (TICs) is essential to explore new therapies for gastric cancer patients. There are reports that gastric TICs can be identified using the cell surface marker CD44 and that they form floating spheres in culture, but we could not obtain consistent results with our patient-derived tumor xenograft (PDTX) cells. We thus searched for another marker for gastric TICs, and found that CD49fhigh cells from newly-dissected gastric cancers formed tumors with histological features of parental ones while CD49flow cells did not when subcutaneously injected into immunodeficient mice. These results indicate that CD49f, a subunit of laminin receptors, is a promising marker for human gastric TICs. We established a primary culture system for PDTX cells where only CD49fhigh cells could grow on extracellular matrix (ECM) to form ECM-attaching spheres. When injected into immunodeficient mice, these CD49fhigh sphere cells formed tumors with histological features of parental ones, indicating that only TICs could grow in the culture system. Using this system, we found that some sphere-forming TICs were more resistant than gastric tumor cell lines to chemotherapeutic agents, including doxorubicin, 5-fluorouracil and doxifluridine. There was a patient-dependent difference in the tumorigenicity of sphere-forming TICs and their response to anti-tumor drugs. These results suggest that ECM plays an essential role for the growth of TICs, and that this culture system will be useful to find new drugs targeting gastric TICs.

Gastric cancer stem cells: evidence, potential markers, and clinical implications

“…Two studies, however, were unable to demonstrate stem cell properties in the CD44? purified subset of patient-derived gastric cancer cells, perhaps due to inappropriate microenvironments in mouse models [73,74]. CSC populations have also been identified using a combination of CD44?…”

“…However, other, more specific markers are needed in addition to EpCAM, as the majority of gastric cancer cells are EpCAM-positive. CD49f, a subunit of laminin receptors, has been used to isolate CSCs in prostate, breast, brain, and colon cancer [74]. Fukamachi et al [74] demonstrated CSC properties of self-renewal, heterogeneous lineage, and chemotherapy resistance in the CD49f-selected cells from primary gastric cancer mouse xenografts.…”

Surface Antigen Profiling of Helicobacter pylori‐Infected and ‐Uninfected Gastric Cancer Cells Using Antibody Microarray

“…Upregulation of CD49f in all types of samples examined, but not cagAÀ H. pyloriinfected cells indicate the importance of this antigen in initial carcinogenesis of gastric cancer and also in CagA protein pathogenesis. Cells with high expression of CD49f, CD29, and CD24 have been shown to possess higher metastatic ability [36] and are more durable to chemotherapy drug [37]. Not surprisingly, CD49f is marker for cancer stem cells [37,38] while CD55 has been shown to be repressed in H. pylorieradicated patients [39].…”

“…Cells with high expression of CD49f, CD29, and CD24 have been shown to possess higher metastatic ability [36] and are more durable to chemotherapy drug [37]. Not surprisingly, CD49f is marker for cancer stem cells [37,38] while CD55 has been shown to be repressed in H. pylorieradicated patients [39]. Induction of stem cell markers in gastric epithelial cells infected with cagA+ H. pylori confers the importance of cell stemness during initial infection of H. pylori.…”

Potential role of cancer stem cells as biomarkers and therapeutic targets in cervical cancer

“…74 Studies have shown that CD49f is not only upregulated in breast cancer but also in other cancer types like gastric, colon, and prostate cancers and is responsible for maintaining the stemness of these cancer cells. 49,75,76 Furthermore, tumor spheroids of cervical CSCs expressing high levels of CD49F have been shown to be resistant to radiation therapy. 7 Table 2 lists the several SC markers identified for screening of cervical cancer.…”