Abstract
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.
Highlights
Recent cancer incidence and mortality statistics indicate an always increasing burden of cancer in the coming years, with most new cases occurring in countries of low and middle income [1,2,3]
Epigenetic drugs including histone deacetylase (HDAC) inhibitors are under investigation for their effect on several signaling pathways such as the JAK-STAT pathway in both cancer cells and cancer-associated fibroblasts (CAFs) [443]
Another appealing strategy include the use of normal fibroblasts in cancer treatment or the reversion of activated CAFs to normal fibroblasts [445]
Summary
Recent cancer incidence and mortality statistics indicate an always increasing burden of cancer in the coming years, with most new cases occurring in countries of low and middle income [1,2,3]. CAFs will eventually become the dominant stromal cell type within the TM and promote tumor progression via release of several factors and the synthesis of the ECM [17, 18, 24, 55, 57] Irrespective of their cell of origin, CAFs are large spindle shaped cells showing increased stress fibres and well developed cellular-extracellular matrix connections [59]. Involved in maintenance of cellular cell structure, α-SMA is involved in the migration and contraction of cells Another CAF marker vimentin is expressed highly by CAFs in breast and prostate cancers [55, 103]. I utilised the publicly available The Cancer Genomic Atlas (TCGA) (http://cancergenome.nih.gov.) and Gene Expression Profiling Interactive Analysis (GEPIA) (http://gepia.cancer-pku.cn.) databases to evaluate the expression of several CAF markers in tumor samples compared to normal samples
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