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Published on: November 19, 2019
Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice
Ling Li1, Xinbao Hao2, Jun Qin3
1Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.
Background & Aims:
CD44s is a surface marker of tumor-initiating cells (TICs); high tumor levels correlate with metastasis and recurrence, as well as poor outcomes for patients. Monoclonal antibodies against CD44s might eliminate TICs with minimal toxicity. This strategy is unclear for treatment of pancreatic cancer, and little is known about how anti-CD44s affect pancreatic cancer initiation or recurrence after radiotherapy.
Methods:
One hundred ninety-two pairs of human pancreatic adenocarcinoma and adjacent nontumor pancreatic tissues were collected from patients undergoing surgery. We measured CD44s levels in tissue samples and pancreatic cancer cell lines by immunohistochemistry, real-time polymerase chain reaction, and immunoblot; levels were correlated with patient survival times. We studied the effects of anti-CD44s in mice with human pancreatic tumor xenografts and used flow cytometry to determine the effects on TICs. Changes in CD44s signaling were examined by real-time polymerase chain reaction, immunoblot, reporter assay, and in vitro tumorsphere formation assays.
Results:
Levels of CD44s were significantly higher in pancreatic cancer than adjacent nontumor tissues. Patients whose tumors expressed high levels of CD44s had a median survival of 10 months compared with >43 months for those with low levels. Anti-CD44s reduced growth, metastasis, and postradiation recurrence of pancreatic xenograft tumors in mice. The antibody reduced the number of TICs in cultured pancreatic cancer cells and xenograft tumors, as well as their tumorigenicity. In cultured pancreatic cancer cell lines, anti-CD44s down-regulated the stem cell self-renewal genes Nanog, Sox-2, and Rex-1 and inhibited signal transducer and activator of transcription 3-mediated cell proliferation and survival signaling.
Conclusions:
The TIC marker CD44s is up-regulated in human pancreatic tumors and associated with patient survival time. CD44s is required for initiation, growth, metastasis, and postradiation recurrence of xenograft tumors in mice. Anti-CD44s eliminated bulk tumor cells as well as TICs from the tumors. Strategies to target CD44s cab be developed to block pancreatic tumor formation and post-radiotherapy recurrence in patients.
Insights
Targeting the CD44s marker, a key component of tumor-initiating cells (TICs), shows promise for pancreatic cancer treatment. Anti-CD44s antibodies effectively reduced tumor growth, metastasis, and recurrence in preclinical models.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Immunotherapy
Background:
- CD44s is a surface marker associated with tumor-initiating cells (TICs), correlating with pancreatic cancer metastasis, recurrence, and poor patient outcomes.
- Monoclonal antibodies targeting CD44s offer a potential strategy to eliminate TICs with minimal toxicity, though their efficacy in pancreatic cancer, especially post-radiotherapy, requires further investigation.
Purpose of the Study:
- To investigate the role of CD44s in pancreatic cancer initiation and recurrence.
- To evaluate the therapeutic potential of anti-CD44s antibodies in pancreatic cancer models, including their impact on TICs and post-radiotherapy recurrence.
Main Methods:
- Analysis of CD44s expression in 192 human pancreatic adenocarcinoma tissues and cell lines using immunohistochemistry, real-time PCR, and immunoblotting.
- Correlation of CD44s levels with patient survival.
- In vivo studies using human pancreatic tumor xenografts in mice treated with anti-CD44s antibodies, assessing tumor growth, metastasis, and post-radiation recurrence.
- Flow cytometry and in vitro assays (tumorsphere formation) to evaluate effects on TICs and CD44s signaling pathways (Nanog, Sox-2, Rex-1, STAT3).
Main Results:
- CD44s was significantly upregulated in pancreatic tumors compared to adjacent non-tumor tissues, with high levels correlating to shorter patient survival (10 months vs. >43 months).
- Anti-CD44s treatment reduced xenograft tumor growth, metastasis, and post-radiation recurrence in mice.
- The antibody decreased TIC populations and their tumorigenicity, downregulating stem cell renewal genes (Nanog, Sox-2, Rex-1) and inhibiting STAT3 signaling.
Conclusions:
- CD44s is a crucial marker for pancreatic cancer initiation, growth, metastasis, and post-radiotherapy recurrence.
- Anti-CD44s antibodies effectively eliminate both bulk tumor cells and TICs.
- Targeting CD44s presents a promising therapeutic strategy to prevent pancreatic tumor formation and recurrence after radiotherapy.
