CD13 is a therapeutic target in human liver cancer stem cells

Haraguchi, Naotsugu; Ishii, Hideshi; Mimori, Koshi; Tanaka, Fumiaki; Ohkuma, Masahisa; Kim, Ho Min; Akita, Hirofumi; Takiuchi, Daisuke; Hatano, Hisanori; Nagano, Hiroaki; Barnard, Graham F.; Doki, Yuichiro; Mori, Masaki

doi:10.1172/jci42550

Cited by 554 publications

(514 citation statements)

References 39 publications

Supporting

Mentioning

502

Contrasting

Order By: Relevance

“…The importance of APN expression by malignant cells in primary tumors and metastases is also supported by clinical studies (9). Recently, APN has been described as a surface marker for tumor-initiating cells in human liver cancer cell lines and in clinical samples (41). Whether APN functions as a marker of tumor-initiating cells in the systems studied in this work remains to be determined.…”

Section: Discussionmentioning

confidence: 92%

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Guzman-Rojas

Rangel

Salameh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

115

View full text Add to dashboard Cite

Processes that promote cancer progression such as angiogenesis require a functional interplay between malignant and nonmalignant cells in the tumor microenvironment. The metalloprotease aminopeptidase N (APN; CD13) is often overexpressed in tumor cells and has been implicated in angiogenesis and cancer progression. Our previous studies of APN-null mice revealed impaired neoangiogenesis in model systems without cancer cells and suggested the hypothesis that APN expressed by nonmalignant cells might promote tumor growth. We tested this hypothesis by comparing the effects of APN deficiency in allografted malignant (tumor) and nonmalignant (host) cells on tumor growth and metastasis in APNnull mice. In two independent tumor graft models, APN activity in both the tumors and the host cells cooperate to promote tumor vascularization and growth. Loss of APN expression by the host and/ or the malignant cells also impaired lung metastasis in experimental mouse models. Thus, cooperation in APN expression by both cancer cells and nonmalignant stromal cells within the tumor microenvironment promotes angiogenesis, tumor growth, and metastasis.lung cancer | melanoma | proteolytic activity | shRNA | tumorigenesis A minopeptidase N (APN, CD13; EC 3.4.11.2) is a widely expressed type II membrane-bound metalloprotease (1, 2). It functions in the enzymatic cleavage of peptides, in endocytosis, and as a signaling molecule and has been implicated in the regulation of complex and diverse processes, including cell migration, cell survival, viral uptake, and angiogenesis (3). APN has also been linked specifically to cancer, having been identified as a cellsurface marker for malignant myeloid cells (4-7) and reaching high levels of expression in association with the progression of tumors, including breast, ovarian, and prostate cancer (8-14). Indeed, vascular endothelial growth factor (VEGF), a key angiogenesis regulator, induces the expression of APN at an early stage of tumor growth (15), again highlighting the role of this enzyme in angiogenesis, a process crucial for sustained growth of most solid tumors (16). Studies of bestatin, a CD13 inhibitor and antiangiogenic agent, also suggest that APN enzymatic activity is relevant for tumorigenesis (17,18). Nevertheless, the substrates of APN in the context of angiogenesis are still unknown. The only well-defined substrate is angiotensin III in the renin-angiotensin pathway, in which APN cleaves the NH 2 -terminal arginine residue of angiotensin III to form angiotensin IV. Consistent with several lines of evidence, we have previously identified APN as a target for inhibition of tumor vascularization and growth (18)(19)(20).Tumor growth relies on a complex microenvironment in which malignant cells cooperate with various other cell types: endothelial cells of the blood and lymphatic circulation, mesenchymal stromal cells/cancer-associated fibroblasts, and a variety of bone marrow-derived cells such as myeloid-derived suppressor cells and lymphocytes (21, 22). Some of these cell populations c...

show abstract

Section: Discussionmentioning

confidence: 92%

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Guzman-Rojas

Rangel

Salameh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

115

View full text Add to dashboard Cite

show abstract

“…CSCs, which represent a small population of tumor cells, are capable of selfrenewal and can proliferate and differentiate into heterogeneous lines of cancer cells. 12 Hepatic CSCs were first reported by Haraguchi et al 13 CSCs appear to arise by an epigenetic mechanism, 14 and in recent years, several important biomarkers of hepatic CSCs, such as CD90, 15 CD133, 16 epithelial cell adhesion molecule 17 and CD13, 18 have been identified. These markers are crucial for the identification and isolation of CSCs.…”

Section: Introductionmentioning

confidence: 99%

Attenuated Listeria monocytogenes as a cancer vaccine vector for the delivery of CD24, a biomarker for hepatic cancer stem cells

Hou

Zhe

et al. 2014

Cell Mol Immunol

View full text Add to dashboard Cite

Attenuated Listeria monocytogenes (LM) is a promising candidate vector for the delivery of cancer vaccines. After phagocytosis by antigen-presenting cells, this bacterium stimulates the major histocompatibility complex (MHC)-I and MHC-II pathways and induces the proliferation of antigen-specific T lymphocytes. A new strategy involving genetic modification of the replication-deficient LM strain DdalDdat (Lmdd) to express and secrete human CD24 protein has been developed. CD24 is a hepatic cancer stem cell biomarker that is closely associated with apoptosis, metastasis and recurrence of hepatocellular carcinoma (HCC). After intravenous administration in mice, Lmdd-CD24 was distributed primarily in the spleen and liver and did not cause severe organ injury. Lmdd-CD24 effectively increased the number of interferon (IFN)-c-producing CD8 1 T cells and IFN-c secretion. Lmdd-CD24 also enhanced the number of IL-4-and IL-10-producing T helper 2 cells. The efficacy of the Lmdd-CD24 vaccine was further investigated against Hepa1-6-CD24 tumors, which were inguinally inoculated into mice. Lmdd-CD24 significantly reduced the tumor size in mice and increased their survival. Notably, a reduction of T regulatory cell (Treg) numbers and an enhancement of specific CD8 1 T-cell activity were observed in the tumor-infiltrating lymphocytes (TILs). These results suggest a potential application of the Lmdd-CD24 vaccine against HCC.

show abstract

“…ROS Assay-The ROS assay was performed as described previously (12). Intracellular ROS levels were determined by incubating the cells for 30 min at 37°C with 5 M CellROX Deep Red reagent (Invitrogen) in complete medium, followed by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

RFPL4A Increases the G1 Population and Decreases Sensitivity to Chemotherapy in Human Colorectal Cancer Cells

Naito¹,

Yamamoto

Kagawa

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Cell cycle-arrested cancer cells are resistant to conventional chemotherapy. Results: Microarray analyses showed that expression of RFPL4A was significantly up-regulated in these G 1 -retained cells. Conclusion: RFPL4A is a novel factor inducing G 1 retention and reduced sensitivity to chemotherapy. Significance: Combination therapy using RFPL4A inhibition and conventional anti-cancer drugs may represent a promising therapeutic approach for intractable cancer patients.

show abstract

CD13 is a therapeutic target in human liver cancer stem cells

Cited by 554 publications

References 39 publications

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Attenuated Listeria monocytogenes as a cancer vaccine vector for the delivery of CD24, a biomarker for hepatic cancer stem cells

RFPL4A Increases the G1 Population and Decreases Sensitivity to Chemotherapy in Human Colorectal Cancer Cells

Contact Info

Product

Resources

About