Abstract 511: The role of hyaluronan-CD44 interaction in breast cancer.
Anne KulttiSusan ZimmermanLei HuangYanling ChenJessica CowellRebecca SymonsLaurence JadinPing JiangG. J. FrostMichael ShepardJohn Huang
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Abstract The tumor microenvironment is crucial for cancer cell survival and spreading. The glycosaminoglycan hyaluronan (HA) is accumulated in 50% of malignant breast cancer tumors and its accumulation correlates with poor survival of breast cancer patients. HA is synthesized at the cell surface by HA synthase enzymes (HAS1-3) and is extruded to the extracellular space where HA molecules can be attached to the cell surface via interactions with its receptors or HAS proteins. HA can also interact with its binding proteins and be incorporated into surrounding ECM. However, the origin and exact functions of HA in breast cancer are still unclear. The aim of this study was to explore the role of HA in the tumor microenvironment of breast cancer, especially in the interaction of tumor and stromal cells in vitro and in vivo. First, interaction of breast cancer cells and stromal cells were studied in mono- and co-cultures. Human bone marrow-derived mesenchymal stem cells (MSCs) and breast cancer-associated fibroblasts (CAFs) synthesized high amounts of HA, while this was the case for <5% MDA-MB-468 breast cancer cells. In co-culture with MSCs or CAFSs, MDA-MB-468 and MDA-MB-231 cells formed distinct pericellular HA coats. Similar HA coats were observed after addition of exogenous FITC-labeled high molecular weight HA (1,2 MDa) to MDA-MB-468 and MDA-MB-231 cell cultures. Interestingly, binding of FITC-labeled HA was not efficiently blocked by unlabeled HA below 500 kDa. In co-cultures, the high molecular weight HA coats around MDA-MB-468 and MDA-MB-231 cells were prevented by antibody blockade of the HA receptor CD44, indicating that formation of HA coats is CD44-mediated. Knockdown of CD44 by shRNA also inhibited the formation of HA coats when FITC-HA was added to the cultures or when breast cancer cells were co-cultured with MSCs. MSCs also increased proliferation and migration of MDA-MB-468 (parental/Luc) cells, analyzed by luciferin and Transwell migration assays, respectively. MDA-MB-468 cell proliferation was slightly inhibited by removal of HA with pegylated human recombinant hyaluronidase PH20 (PEGPH20), and migration towards exogenous HA could be inhibited by CD44 knockdown. Importance of HA coats around breast cancer cells was also studied in vivo using MDA-MB-468 cells over-expressing HAS3 which forms 4.7-fold larger HA coats than parental MDA-MB-468 cells. MDA-MB-468 HAS3 cells exhibited much enhanced in vivo growth compared to MDA-MB-468 cells, and tumor growth of MDA-MB-468 HAS3 xenografts was inhibited up to 85% by PEGPH20. The results suggest that HA in tumor microenvironment, produced by tumor or stromal cells, provides growth benefit for breast cancer cells via promoting their proliferation and migration. Both phenomena seem to be mediated by CD44, which highlights the importance of HA-CD44 interaction in the growth of breast cancer. Citation Format: Anne Kultti, Susan Zimmerman, Lei Huang, Yanling Chen, Jessica Cowell, Rebecca C. Symons, Laurence Jadin, Ping Jiang, Gregory I. Frost, Michael Shepard, John Huang. The role of hyaluronan-CD44 interaction in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 511. doi:10.1158/1538-7445.AM2013-511Keywords:
Cancer-Associated Fibroblasts
Cancer-associated fibroblasts (CAFs) and tumor-infiltrating immune cells are the most essential components of the tumor microenvironment (TME). They communicate with each other in tumor microenvironment and play a critical role in tumorigenesis and development. CAFs are very heterogeneous and different subtypes of CAFs display different functions. At the same time, it can contribute to the regulation of the function of tumor-infiltrating immune cells and eventually result in the carcinogenesis, tumor progression, invasion, metastasis and other biological behaviors of tumors by producting various growth factors and cytokines etc. Based on the current research results at home and abroad, this paper reviews the recent research progress on the regulation of CAFs on infiltrating immune cells in tumor microenvironment. .【中文题目：肿瘤相关成纤维细胞对于免疫细胞的 调节作用研究现状】 【中文摘要：肿瘤相关成纤维细胞（cancer-associated fibroblasts, CAFs）和肿瘤浸润性免疫细胞是肿瘤微环境（tumor microenvironment, TME）中重要的组成成分。二者在肿瘤微环境中相互通信，在肿瘤的发生和发展中发挥着重要作用。CAFs具有很大的异质性，不同的CAFs亚群存在着不同的功能。同时其又可以通过分泌多种细胞因子、趋化因子等方式实现对肿瘤浸润性免疫细胞的调节，从而进一步影响肿瘤的发生、发展、侵袭、转移等生物学行为。本文对国内外近年来有关CAFs在TME中对浸润性免疫细胞调节作用的研究现状作一综述。 】 【中文关键词：肿瘤微环境；肿瘤相关成纤维细胞；肿瘤浸润型免疫细胞；免疫调节；肿瘤免疫】.
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Immunotherapy for solid tumors has shown promise in preclinical as well as early clinical studies. However, its efficacy remains limited. The hindrance to achieving objective, long-lasting therapeutic responses in solid tumors is, in part, mediated by the dynamic nature of the tumor and its complex microenvironment. Tumor-directed therapies fail to eliminate components of the microenvironment, which can reinstate a tumorigenic milieu and contribute to recurrence. Cancer-associated fibroblasts (CAFs) form the most preponderant cell type in the solid tumor microenvironment. Given their pervasive role in facilitating tumor growth and metastatic dissemination, CAFs have emerged as attractive therapeutic targets in the tumor microenvironment. In this article, we highlight the cross-talk between CAFs and cancer cells, and discuss how targeting CAFs has the potential to improve current immunotherapy approaches for cancer.
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Non-small cell lung cancer (NSCLC) has a markedly poor prognosis as it progresses, and the prognosis is still unsatisfactory even with modern treatments. Cancer is composed of not only cancer cells, but also stroma consisting of various cell types. Cancer-associated fibroblasts (CAFs) are a major component of the stroma and the associated tumor microenvironment (TME). Particularly, CAFs are a critical component in elucidating the biological mechanisms of cancer progression and new therapeutic targets. This article outlines the TME formed by CAFs in NSCLC.Focusing on the TME in NSCLC, we discuss the mechanisms by which CAFs are involved in cancer progression, drug resistance, and the development of therapies targeting CAFs.In the TME, CAFs profoundly contribute to tumor progression by interacting with cancer cells through direct contact or paracrine cytokine signaling. CAFs also interact with various other stromal components to establish a tumor-promoting immunosuppressive microenvironment and remodel the extracellular matrix. Furthermore, these effects are closely associated with drug resistance. Further elucidation of the stromal microenvironment, including CAFs, could prove to be crucial in the treatment of NSCLC.
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Tumor immune infiltration plays a key role in the progression of solid tumors, including ovarian cancer, and immunotherapies are rapidly emerging as effective treatment modalities. However, the role of cancer-associated fibroblasts (CAFs), a predominant stromal constituent, in determining the tumor-immune microenvironment and modulating efficacy of immunotherapies remains poorly understood. We have conducted an extensive bioinformatic analysis of our and other publicly available ovarian cancer datasets (GSE137237, GSE132289 and GSE71340), to determine the correlation of fibroblast subtypes within the tumor microenvironment (TME) with the characteristics of tumor-immune infiltration. We identified (1) four functional modules of CAFs in ovarian cancer that are associated with the TME and metastasis of ovarian cancer, (2) immune-suppressive function of the collagen 1,3,5-expressing CAFs in primary ovarian cancer and omental metastases, and (3) consistent positive correlations between the functional modules of CAFs with anti-immune response genes and negative correlation with pro-immune response genes. Our study identifies a specific fibroblast subtype, fibroblast functional module (FFM)2, in the ovarian cancer tumor microenvironment that can potentially modulate a tumor-promoting immune microenvironment, which may be detrimental toward the effectiveness of ovarian cancer immunotherapies.
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The tumor microenvironment is a system with different characteristics from the normal tissue microenvironment.Carcinoma-associated fibroblasts (CAFs) are the most important cells in tumor microenvironment.Characteristics of the fibroblasts in the oral cancer microenvironment are different from the normal fibroblast cells.The fibroblasts in the oral cancer microenvironment play an important role in cancerogenesis,development,and metastasis.
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Close interactions between cancer cells and cancer-associated fibroblasts (CAF) have repeatedly been reported to support tumor progression. Yet, targeting CAFs has so far failed to show a real benefit in cancer treatment, as preclinical studies have shown that such a strategy can enhance tumor growth. Accordingly, recent paradigm-shifting data suggest that certain CAF subpopulations could also show tumor-inhibitory capabilities. The present review aims to provide an in-depth description of the cellular heterogeneity of the CAF compartment in tumors. Through combining information from different cancer types, here we define 4 main CAF subpopulations that might cohabitate in any tumor microenvironment (TME). In addition, a model for the evolution of CAFs during tumor development is introduced. Moreover, the presence of tumor-inhibitory CAFs in the TME as well as their molecular characteristics are extensively discussed. Finally, the potential cellular origins of these distinct CAF subpopulations are reviewed. To our knowledge, this is the first attempt at establishing a broad but comprehensive classification of CAF subpopulations. Altogether, the present manuscript aims to provide the latest developments and innovative insights that could help refine future therapeutic targeting of CAFs for cancer treatment.
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Cancer-Associated Fibroblasts
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Cancers are heterogeneous tissues comprised of multiple components, including tumor cells and microenvironment cells. The tumor microenvironment has a critical role in tumor progression. The tumor microenvironment is comprised of various cell types, including fibroblasts, macrophages and immune cells, as well as extracellular matrix and various cytokines and growth factors. Fibroblasts are the predominant cell type in the tumor microenvironment. However, neither the derivation of tissue-specific cancer-associated fibroblasts nor markers of tissue-specific cancer-associated fibroblasts are well defined. Despite these uncertainties it is increasingly apparent that cancer-associated fibroblasts have a crucial role in tumor progression. In breast cancer, there is evolving evidence showing that breast cancer-associated fibroblasts are actively involved in breast cancer initiation, proliferation, invasion and metastasis. Breast cancer-associated fibroblasts also play a critical role in metabolic reprogramming of the tumor microenvironment and therapy resistance. This review summarizes the current understanding of breast cancer-associated fibroblasts.
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Cancer-associated fibroblasts (CAFs), enriched in the tumor stroma, have received increasing attention because of their multifaceted effects on tumorigenesis, development, metastasis, and treatment resistance in malignancies. CAFs contributed to suppressive microenvironment via different mechanisms, while CAFs also exerted some antitumor effects. Therefore, CAFs have been considered promising therapeutic targets for their remarkable roles in malignant tumors. However, patients with malignancies failed to benefit from current CAFs-targeted drugs in many clinical trials, which suggests that further in-depth investigation into CAFs is necessary. Here, we summarize and outline the heterogeneity and plasticity of CAFs mainly by exploring their origin and activation, highlighting the regulation of CAFs in the tumor microenvironment during tumor evolution, as well as the critical roles performed by CAFs in tumor immunity. In addition, we summarize the current immunotherapies targeting CAFs, and conclude with a brief overview of some prospects for the future of CAFs research in the end. Video Abstract.
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