Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab

Our plain-English summary of Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab, by A. Mitsuhashi, H. Goto, A. Saijo, et al (Nature Communications, 2015).

The study

• Authors: A. Mitsuhashi, H. Goto, A. Saijo, V.T. Trung, Y. Aono, H. Ogino, T. Kuramoto, S. Tabata, H. Uehara, K. Izumi, M. Yoshida, H. Kobayashi, H. Takahashi, M. Gotoh, S. Kakiuchi, M. Hanibuchi, S. Yano, H. Yokomise, S. Sakiyama, Y. Nishioka
• Journal: Nature Communications
• Published: 2015;6:8792
• Cited by: 66 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy.

In plain English

This laboratory study combined mouse tumour experiments with staining of human lung cancer tissue to ask how tumours become resistant to the anti-VEGF antibody bevacizumab. Immunodeficient mice were given human malignant pleural mesothelioma cells (Y-MESO-14, EHMES-10) or human lung adenocarcinoma cells (PC14PE6, A549) and treated continuously with bevacizumab from day 7. The authors reported that bevacizumab prolonged survival in all four models (Y-MESO-14 P=0.0355; EHMES-10 P=0.0046; PC14PE6 P=0.0002), although the A549 comparison did not reach statistical significance (P=0.0780); microvessel density first fell and then rose again over time, which the authors read as acquired resistance. Mouse (stromal) FGF2 rose in treated tumours, and cells positive for both collagen type I and CXCR4, called fibrocyte-like cells and shown by bone marrow transplant to come from bone marrow, increased and produced FGF2. Adding an FGFR inhibitor or a CXCR4 inhibitor to bevacizumab further reduced vessel density. In 26 resected lung adenocarcinomas (10 treated with bevacizumab-containing chemotherapy), CD45+/FSP-1+ cells were higher after bevacizumab and correlated with treatment cycles (P=0.0058, r=0.8200) and vessel length (P=0.0323, r=0.5033).

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Experimental animal (mouse xenograft and syngeneic) study with in vitro cell work and immunohistochemistry of human surgical specimens
• Who was studied: Immunodeficient (SCID and nude) mice bearing human mesothelioma or lung cancer cell lines, C57BL/6 mice with B16 melanoma, and paraffin sections from 26 lung adenocarcinoma patients in Japan
• Exposure: Continuous bevacizumab treatment (10 mg per mouse twice weekly from day 7; patients received bevacizumab-containing neoadjuvant chemotherapy), alone or combined with the FGFR inhibitor BGJ-398, FGF2-neutralizing antibody, or the CXCR4 antagonist AMD3100; SU5416 in the B16 model
• Main results:
  • Bevacizumab prolonged survival of tumour-bearing mice in all four cell line models, with the A549 comparison not reaching significance
  • Microvessel density fell with bevacizumab but rose again over time with continued treatment, interpreted by the authors as acquired resistance
  • Mouse FGF2 protein was significantly increased in pleural effusion of bevacizumab-treated Y-MESO-14 tumour-bearing mice; mouse VEGF-A rose 1.4-fold but not significantly
  • Combining the FGFR inhibitor BGJ-398 with bevacizumab further prolonged survival of Y-MESO-14 tumour-bearing mice
  • By flow cytometry of mouse tumours, the percentage of CD45+/collagen type I+/CXCR4+ fibrocyte-like cells was significantly increased in bevacizumab-resistant tumours
  • In mouse tumours, Gr-1+ MDSCs were unchanged and F4/80+ macrophages slightly increased with bevacizumab
  • In the human specimens, CD45+/FSP-1+ cells were higher in tumours of patients given bevacizumab-containing chemotherapy than in the other two groups
  • In bevacizumab-treated patients, the number of CD45+/FSP-1+ cells correlated with bevacizumab treatment cycles and with intratumoural vessel length
  • Correlation of CD45+/FSP-1+ cells with bevacizumab treatment cycles in the bevacizumab-treated patients: P=0.0058, r=0.8200
  • Correlation of CD45+/FSP-1+ cells with vessel length in the tumour in the bevacizumab-treated patients: P=0.0323, r=0.5033
• The authors' conclusion: The authors concluded that fibrocyte-like cells may be key regulatory cells in the tumour microenvironment involved in acquiring resistance to anti-VEGF therapy through their production of FGF2
• Limitations the authors state:
  • The main mouse experiments used immunodeficient mice lacking lymphocytes
  • Not all bevacizumab-treated patients had clinically acquired resistance before surgery
  • The authors state that surgically removed samples after bevacizumab treatment are challenging to obtain and few in number, so continued work is warranted
  • The authors state macrophages may also contribute to angiogenesis in their model and their role needs clarification

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Bevacizumab, Collagen, Pleural Mesothelioma, Lung Cancer, Fibroblast, Biomarker.

Related studies

• Current data on predictive markers for anti-angiogenic therapy in thoracic tumours — N. Reinmuth, M. Thomas, et al. (2010)
• Pemetrexed Maintenance Therapy Following Bevacizumab-Containing First-Line Chemotherapy in Advanced Malignant Pleural Mesothelioma: A Case Report and Literatures Review — X.Q. Jing, L. Zhou, et al. (2016)
• Combinatorial anti-angiogenic gene therapy in a human malignant mesothelioma model — S. Kubo, M. Takagi-Kimura, et al. (2015)
• Anti-angiogenic therapies for malignant pleural mesothelioma — G.L. Ceresoli, P.A. Zucali (2012)
• Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report — J. Hu, B. Zhang, et al. (2020)
• A review of bevacizumab in the treatment of malignant pleural mesothelioma — S. Brosseau, S. Assoun, et al. (2017)

Browse more research in Nature Communications, or return to medical research.