Tyrosine kinase inhibitors and mesenchymal stromal cells: effects on self-renewal, commitment and functions

Abstract

The hope of selectively targeting cancer cells by therapy and eradicating definitively malignancies is based on the identification of pathways or metabolisms that clearly distinguish “normal” from “transformed” phenotypes. Some tyrosine kinase activities, specifically unregulated and potently activated in malignant cells, might represent important targets of therapy. Consequently, tyrosine kinase inhibitors (TKIs) might be thought as the “vanguard” of molecularly targeted therapy for human neoplasias. Imatinib and the successive generations of inhibitors of Bcr-Abl1 kinase, represent the major successful examples of TKI use in cancer treatment. Other tyrosine kinases have been selected as targets of therapy, but the efficacy of their inhibition, although evident, is less definite. Two major negative effects exist in this therapeutic strategy and are linked to the specificity of the drugs and to the role of the targeted kinase in non-malignant cells. In this review, we will discuss the data available on the TKIs effects on the metabolism and functions of mesenchymal stromal cells (MSCs). MSCs are widely distributed in human tissues and play key physiological roles; nevertheless, they might be responsible for important pathologies. At present, bone marrow (BM) MSCs have been studied in greater detail, for both embryological origins and functions. The available data are evocative of an unexpected degree of complexity and heterogeneity of BM-MSCs. It is conceivable that this grade of intricacy occurs also in MSCs of other organs. Therefore, in perspective, the negative effects of TKIs on MSCs might represent a critical problem in long-term cancer therapies based on such inhibitors.

How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive

“…Indeed, MSCs bear at the cell surface several receptors that can be considered as targets for tumor cell therapy with TKi. In particular, the expression on MSC of PDGFR-β and EGFR is well established; the effects of TKi such as imatinib, nilotinib, or gefitinib in vitro have pointed out that these drugs can affect both MSC proliferation and differentiation ( 108 – 122 ). These effects have been recently reviewed in very detail ( 122 ).…”

“…In particular, the expression on MSC of PDGFR-β and EGFR is well established; the effects of TKi such as imatinib, nilotinib, or gefitinib in vitro have pointed out that these drugs can affect both MSC proliferation and differentiation ( 108 – 122 ). These effects have been recently reviewed in very detail ( 122 ). It is clear from all these findings that, as expected, TKi can exert a strong inhibition on MSC growth and function, but their effects on MSC-mediated immunosuppression have not been studied.…”

Stem cell programs in cancer initiation, progression, and therapy resistance

“…Also, secretion of high amounts of the chemokine CXCL12 results in increased TGF-β secretion through binding to its receptor CXCR4, which in turn causes EMT, a key step in metastasis. Thus, targeting this signaling axis has shown anti-metastatic potential in vivo 210 - 214 . However, no clinically relevant data is available for the aforementioned targets and new therapeutic strategies are thus required.…”

<p>Tumor necrosis factor &alpha; knockout impaired tumorigenesis in chronic myeloid leukemia cells partly by metabolism modification and miRNA regulation</p>

“…Increasing evidence has shown that specific modes of metabolism play important roles in the self-renewal capacities of both healthy and transformed stem cells 14,15. LSCs demand tightly regulated metabolism since the disruption of either glycolysis or mitochondrial respiration impairs leukemogenesis 16,17.…”