In search of definitions: Cancer‐associated fibroblasts and their markers

Abstract

The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer‐associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor‐modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various “CAF markers”, such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross‐applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting.

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

“…Because CAFs were reported to be a heterogeneous population of fibroblasts. 28 Nonetheless, since our analyses focused on CAFs derived from tumor tissues, which were observed to express CXCL5 significantly, we suggest that the expression of CXCL5 may be the character rather than the symbol of CAFs in melanoma and CRC. In liver cancer, CXCL5 was reported to be a candidate of diagnostic and therapeutic biomarkers with potential clinical values.…”

“…CXCL5 also did not increase together with classical CAF markers under TGF‐β treatment, which may be due in large due to the different compositions between CAFs and those fibroblasts activated by cytokines. Because CAFs were reported to be a heterogeneous population of fibroblasts . Nonetheless, since our analyses focused on CAFs derived from tumor tissues, which were observed to express CXCL5 significantly, we suggest that the expression of CXCL5 may be the character rather than the symbol of CAFs in melanoma and CRC.…”

Tumor microenvironment complexity and therapeutic implications at a glance

“…Cancer-associated fibroblasts (CAFs) in the immediate vicinity of cancer cells play an important role in tumorigenesis in various physicochemical ways by reducing apoptosis and improving the proliferation, migration and viability of cancer cells [58,59]. CAFs residing in TME are heterogeneous cells with different origins, different functions (pro or anti-tumor activities) and different surface markers such as alpha-smooth muscle actin (α-SMA), myosin light chain 9 (MYL9), myosin light chain kinase (MYLK), matrix metalloproteinase 2 (MMP2), decorin (DCN) and collagen type I alpha 2 (COL1A2) [60][61][62][63].…”

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

“…Recently, an immune-histochemical score based on the expression of two proteins specific for CAFs has additionally been able to predict the response to neoadjuvant treatment in rectal cancer [103]. Nevertheless, CAFs have been shown to be highly heterogeneous and better markers are currently needed to identify subtypes and shed light on their potential prognostic/predictive value in CRC [104]. The combination of stroma quantification with a functional activity assessment of CAFs might lead to an improved stroma-based tool for patient stratification [105].…”