International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.
Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
OMICS. 2020 Jun;24(6):314-339. doi: 10.1089/omi.2020.0023.
The tumor stroma, a key component of the tumor microenvironment (TME), is a key determinant of response and resistance to cancer treatment. The stromal cells, extracellular matrix (ECM), and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and therapeutic outcomes. Of the stromal cells present in the TME, much attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and important in cancer initiation, progression, and therapy resistance. Besides releasing several factors, CAFs also synthesize the ECM, a key component of the tumor stroma. In this expert review, we examine the role of CAFs in the regulation of tumor cell behavior and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. Importantly, CAFs display both phenotypic and functional heterogeneity, with significant ramifications on CAF-directed therapies. Principal anti-cancer therapies targeting CAFs take the form of: (1) CAFs' ablation through use of immunotherapies, (2) re-education of CAFs to normalize the cells, (3) cellular therapies involving CAFs delivering drugs such as oncolytic adenoviruses, and (4) stromal depletion via targeting the ECM and its related signaling. The CAFs' heterogeneity could be a result of different cellular origins and the cancer-specific tumor microenvironmental effects, underscoring the need for further multiomics and biochemical studies on CAFs and the subsets. Lastly, we present recent advances in therapeutic targeting of CAFs and the success of such endeavors or their lack thereof. We recommend that to advance global public health and personalized medicine, treatments in the oncology clinic should be combinatorial in nature, strategically targeting both cancer cells and stromal cells, and their interactions.
肿瘤基质是肿瘤微环境（TME）的关键组成部分，是决定癌症治疗反应和耐药性的关键因素。基质细胞、细胞外基质（ECM）和血管影响癌细胞对治疗的反应，并在肿瘤复发和治疗结果中发挥关键作用。在 TME 中存在的基质细胞中，癌症相关成纤维细胞（CAFs）受到了广泛关注，因为它们在癌症的发生、发展和耐药性中最为丰富和重要。除了释放多种因子外，CAFs 还合成 ECM，这是肿瘤基质的关键组成部分。在这篇专家综述中，我们研究了 CAFs 在调节肿瘤细胞行为中的作用，并揭示了 CAF 衍生因子和信号如何影响肿瘤细胞异质性和开发新的抗癌策略。重要的是，CAFs 表现出明显的表型和功能异质性，这对 CAF 定向治疗有重大影响。针对 CAFs 的主要抗癌疗法包括：（1）通过免疫疗法消融 CAFs；（2）通过重新教育 CAFs 使其正常化；（3）涉及 CAFs 递送药物（如溶瘤腺病毒）的细胞疗法；（4）通过靶向 ECM 及其相关信号进行基质耗竭。CAFs 的异质性可能是由于不同的细胞起源和癌症特异性肿瘤微环境效应所致，这强调了需要进一步对 CAFs 和其亚群进行多组学和生化研究。最后，我们介绍了 CAFs 治疗靶点的最新进展及其成功或失败的情况。我们建议，为了促进全球公共卫生和个性化医疗，肿瘤学临床治疗应该是组合性质的，有策略地靶向癌细胞和基质细胞及其相互作用。
