Functional diversity of cancer‐associated fibroblasts in modulating drug resistance

Abstract

Over the past few decades, advances in this field have demonstrated that the complexity of cancer is not only dependent on the intrinsic characteristics of tumor cells but also mainly determined by crosstalk between altered cancer cells and various components of the tumor microenvironment (TME). This complexity has become a considerable obstacle in discovering the specific mechanism(s) underlying treatment failure. Many various cell types are present within the TME, including fibroblasts and endothelial, adipose, mesenchymal, and proinflammatory immune cells. 1 Among these cell types, fibroblasts have emerged as a pivotal effector of cancer metabolism and transformation due to their abundance in the tumor stromal tissue and their diverse biological functions. Fibroblasts usually remain in a quiescent state and are flexibly activated and deactivated in response to changes due to tissue damage and wound healing; this results in the generation of myofibroblasts characterized by the expression of α-smooth muscle actin (α-SMA), a fibroblast marker. 2-4 These activated fibroblasts interact closely with tumor cells through multiple mechanisms and produce different results 5 , therefore they are defined as cancer-associated fibroblasts (CAFs) rather than normal fibroblasts (NFs). Among the tumor-promoting functions of CAFs, their reinforcement of chemoresistance is a crucial component due to the importance of establishing an effective anticancer

Inflammation-Induced Tumorigenesis and Metastasis

“…The simultaneous high levels of these pro-inflammatory cytokines are significantly associated with a poor prognosis of patients with GC [ 75 ]. Studies have reported that CAFs are a heterogeneous cell population consisting of different cell subsets with different functions [ 76 , 77 , 78 ]. According to a report from Öhlund et al [ 79 ], there are two spatially and functionally distinct CAF populations, namely inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs).…”

Enabling high throughput target-based drug discovery in 3D cell cultures through novel bioprinting workflow

“…The possibility of creating consistent 3D cell cultures at quantities suitable for HTS also opens the potential for tissue-relevant co-culture models. Recently, pro-inflammatory signaling by fibroblasts has moved into the focus of cancer treatment research for its contribution to cancer drug resistance 22 . We therefore created 3D dermal fibroblast cultures in our third workflow validation experiment to assess the release of the pro-inflammatory cytokine interleukin 6 (IL-6) following stimulation with bacteria wall segments (lipopolysaccharide, LPS) and compare the activation profile with 2D cultures.…”

Fibroblast Subsets in Intestinal Homeostasis, Carcinogenesis, Tumor Progression, and Metastasis

“…It is well known that CAFs can also facilitate cancer progression by promoting tumor cell resistance to cytotoxic therapies [ 120 , 121 ]. Several studies have demonstrated that certain CAFs in human CRCs are also able to do so.…”