Understanding tumor-stroma interplays for targeted therapies by armed mesenchymal stromal progenitors: the Mesenkillers

Abstract

A tumor represents a complex structure containing malignant cells strictly coupled with a large variety of surrounding cells constituting the tumor stroma (TS). In recent years, the importance of TS for cancer initiation, development, local invasion and metastases has become increasingly clear allowing the identification of TS as one of the possible ways to indirectly target tumors. Inside the heterogeneous stromal cell population, tumor associated fibroblasts (TAF) play a crucial role providing both functional and supportive environments. During both tumor and stroma development, several findings suggest that TAF could be recruited from different sources such as locally derived host fibroblasts, via epithelial/endothelial mesenchymal transitions or from circulating pools of fibroblasts deriving form mesenchymal progenitors, namely mesenchymal stem/stromal cells (MSC). These insights prompted scientists to identify multimodal approaches to target TS by biomolecules, monoclonal antibodies, and more recently via cell based strategies. These latter strategies appear extremely promising, although still associated with debated and unclear findings. This review discusses crosstalk between cancers and their stroma, dissecting specific tumor types, such as sarcoma, pancreatic and breast carcinoma, where stroma plays distinct paradigmatic roles. The recognition of these distinct stromal functions may help in planning effective and safer approaches aimed either to eradicate or to substitute TS by novel compounds and/or MSC having specific killing activities.

Keywords: TAF; TRAIL; Tumor stroma; mesenchymal stem/stromal cells.

Figure 1

The origin of TAF. Tumor associated fibroblasts (TAF) may originate from different sources either by circulating mesenchymal progenitors derived from bone marrow (BM-MSC), adipose tissue (AD-MSC) or from locally recruited fibroblasts. In this latter case, TAF may derive from host normal mesenchymal fibroblasts and from cellular elements deriving form epithelial cells resulting from an epithelial-mesenchymal transition (EMT). Alternatively, TAF may be the result of another transition in which endothelial cells are the precursors: the endothelial mesenchymal transition (EndMT).

Figure 2

Morphological appearance of TAF from a primary lung cancer. Representative experiment of tumor associated fibroblasts (TAF) isolated from a patient with lung tumor by collagenase digestion, in vitro cultured and expanded. The FACS analyses (Panel A) reveal surprising similarities in TAF immunopheno-type in comparison with mesenchymal stromal/stem cells (MSC). In addition, in vitro observations (Panel B; 100 x original magnification) indicate a spindle shape morphology of TAF analogous to MSC.