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Targeting Tumour-Associated Fibroblasts in Cancers.

ABSTRACT: Tumours develop within complex tissue environments consisting of aberrant oncogenic cancer cells, diverse innate and adaptive immune cells, along with structural stromal cells, extracellular matrix and vascular networks, and many other cellular and non-cellular soluble constituents. Understanding the heterogeneity and the complex interplay between these cells remains a key barrier in treating tumours and cancers. The immune status of the pre-tumour and tumour milieu can dictate if the tumour microenvironment (TME) supports either a pro-malignancy or an anti-malignancy phenotype. Identification of the factors and cell types that regulate the dysfunction of the TME is crucial in order to understand and modulate the immune status of tumours. Among these cell types, tumour-associated fibroblasts are emerging as a major component of the TME that is often correlated with poor prognosis and therapy resistance, including immunotherapies. Thus, a deeper understanding of the complex roles of tumour-associated fibroblasts in regulating tumour immunity and cancer therapy could provide new insight into targeting the TME in various human cancers. In this review, we summarize recent studies investigating the role of immune and key stromal cells in regulating the immune status of the TME and discuss the therapeutic potential of targeting stromal cells, especially tumour-associated fibroblasts, within the TME as an adjuvant therapy to sensitize immunosuppressive tumours and prevent cancer progression, chemo-resistance and metastasis.

SUBMITTER: Shah K

PROVIDER: S-EPMC9258494 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Neuroblastoma is the most common extracranial solid tumour in children and is histologically classified by its Schwannian stromal cells. Although having fewer Schwannian stromal cells is generally associated with more aggressive phenotypes, the exact roles of other stromal cells (mainly macrophages and fibroblasts) are unclear. Here, we examined 41 cases of neuroblastoma using immunohistochemistry for the tumour-associated macrophage (TAM) markers CD68, CD163, and CD204, and a cancer-associated fibroblast (CAF) marker, alpha smooth muscle actin (αSMA). Each case was assigned to low/high groups on the basis of the number of TAMs or three groups on the basis of the αSMA-staining area for CAFs. Both the number of TAMs and the area of CAFs were significantly correlated with clinical stage, MYCN amplification, bone marrow metastasis, histological classification, histological type, and risk classification. Furthermore, TAM settled in the vicinity of the CAF area, suggesting their close interaction within the tumour microenvironment. We next determined the effects of conditioned medium of a neuroblastoma cell line (NBCM) on bone marrow-derived mesenchymal stem cells (BM-MSCs) and peripheral blood mononuclear cell (PBMC)-derived macrophages in vitro. The TAM markers CD163 and CD204 were significantly up-regulated in PBMC-derived macrophages treated with NBCM. The expression of αSMA by BM-MSCs was increased in NBCM-treated cells. Co-culturing with CAF-like BM-MSCs did not enhance the invasive ability but supported the proliferation of tumour cells, whereas tumour cells co-cultured with TAM-like macrophages had the opposite effect. Intriguingly, TAM-like macrophages enhanced not only the invasive abilities of tumour cells and BM-MSCs but also the proliferation of BM-MSCs. CXCL2 secreted from TAM-like macrophages plays an important role in tumour invasiveness. Taken together, these results indicate that PBMC-derived macrophages and BM-MSCs are recruited to a tumour site and activated into TAMs and CAFs, respectively, followed by the formation of favourable environments for neuroblastoma progression. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Targeting Tumour-Associated Fibroblasts in Cancers.

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