The Origins and Generation of Cancer-Associated Mesenchymal Stromal Cells: An Innovative Therapeutic Target for Solid Tumors

Abstract

Cancer-associated mesenchymal stromal cells (CA-MSCs) have been isolated from various types of tumors and are characterized by their vigorous pro-tumorigenic functions. However, very little is known about the origins and generating process of CA-MSCs, which may facilitate the identification of biomarkers for diagnosis or innovative targets for anti-cancer therapy to restrain the tumor growth, spread and chemotherapy resistance. Current evidences have indicated that both distally recruited and local resident MSCs are the primary origins of CA-MSCs. In a tissue type-dependent mode, tumor cells together with the TME components prompt the malignant transition of tumor “naïve” MSCs into CA-MSCs in a direct cell-to-cell contact, paracrine or exosome-mediated manner. In this review, we discuss the transition of phenotypes and functions of naïve MSCs into CA-MSCs influenced by tumor cells or non-tumor cells in the TME. The key areas remaining poorly understood are also highlighted and concluded herein.

Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer

“…Recently, increasing evidence highlights that ASCs/MSCs are educated and de-differentiated by cancer cells and the TME, fueling malignancy and therapy resistance [ 226 , 227 ]. Cancer-cell-secreted factors and direct cancer cell–ASC/MSC contacts induce a pro-tumorigenic population of ASCs/MSCs, named cancer-associated MSCs (CA-MSCs) [ 143 ].…”

“…In line with this observation, there was evidence suggesting that cancer-released TGFβ was able to activate the Smad signaling pathway in MSCs, which drove differentiation into a cancer-associated phenotype [ 230 ]. In other tumor entities, including lymphomas [ 115 ], lung [ 215 ], and gastric cancer [ 231 , 232 ], IL6, IL8, IL17, IL23, and TNFα secreted by monocytes, macrophages, neutrophils, and non-MSC stromal cells were shown to be capable of promoting malignant transition of ASCs/MSCs, which was associated with significantly increased metastatic rates and tumor growth [ 115 , 215 , 227 , 231 , 232 ]. Other molecular mechanisms proposed for CAF activation include Notch/Eph-ephrin signaling, ECM composition in the TME, DNA damage, physiological stress, inflammatory stimuli, RTK ligands, and TGFβ-mediated signaling [ 34 ].…”

Genomic Analysis Made It Possible to Identify Gene-Driver Alterations Covering the Time Window between Diagnosis of Neuroblastoma 4S and the Progression to Stage 4

“…All NB cells express the GD2 ganglioside; however, this marker is also expressed by CAF-MSC (cancer-associated fibroblast–mesenchymal stromal cells) which are an important source of exosomes [ 32 ]. These GD2 + exosomes, not derived from NB, did not affect the interpretation of the genetic results as they carry normal DNA, free from both chromosomal and gene mutations [ 33 ].…”

“…Since high levels of expression of the KLRB1 gene seem to correspond to better survival of NB patients with normal MYCN status, the loss of KLRB1 —and therefore, the decrease/lack of the specific receptor—probably leads to a failure of NK cells to recognize NB cells, thus promoting tumor growth and progression in the absence of MNA, as in the present case. A novel role of the FANCA gene other than in the DNA repair pathway has recently been described [ 33 ]. A high expression of the FANCA gene determines a worse prognosis in the chronic lymphocytic leukemia as it impairs p53 function [ 39 ].…”

Mesenchymal Stem/Stromal Cells May Decrease Success of Cancer Treatment by Inducing Resistance to Chemotherapy in Cancer Cells

“…It has been shown that the tumour stroma, which is comprised of MSCs, tumour vasculature, infiltrating inflammatory and immune cells, extracellular matrix, and fibroblasts, plays a crucial role in tumour initiation, progression, and metastasis [ 19 , 20 ]. Furthermore, MSCs are one of the crucial stromal cells in the tumour microenvironment, and their interactions with tumour cells and various other components of the tumour microenvironment lead to the transformation from naïve MSCs to tumour-associated MSCs [ 21 , 22 ]. The latter are implicated in tumour growth and progression as well as the development of chemoresistance in cancer cells [ 23 , 24 , 25 ].…”