To grab the stroma by the horns: from biology to cancer therapy with mesenchymal stem cells

Abstract

Mesenchymal stem or stromal cells (MSCs) are precursor cells that play important roles in tumorigenesis. MSCs are recruited to tumors from local and distant sources to form part of the tumor microenvironment. MSCs influence tumor progression by interacting with cancer cells, endothelial cells, immune cells, and cancer stem cells, in a context-dependent network. This review aims to synthesize this emerging yet controversial field to identify key questions regarding the mechanisms of MSC mobilization and survival in blood; homing to tumors, metastases, and premetastatic sites; spatiotemporal organization and differentiation; and interaction with immune cells and cancer stem cells. Understanding the fundamental biology underlying mesenchymal stem cell and tumor interactions has the potential to inform our knowledge of cancer initiation and progression as well as lead to novel therapeutics for cancer. Furthermore, knowledge of endogenous mechanisms can be used to "program" exogenous MSCs for targeted chemotherapeutic delivery to tumors and metastases. Emerging studies will provide crucial insight into the mechanisms of tumor interactions with the whole organism including MSCs.

Figure 1. MSCs are recruited to tumors from local and distant (systemic) sources

Red arrows show regulatory interactions of tumor cells on MSC biology; dark blue arrows show cell movements and action of MSCs on tumor cells. (a) Although the precise mechanisms remain to be determined, local (tissue-resident) MSCs can be recruited to tumors via tumor-derived cytokines, chemokines, and growth factors. (b) In addition, MSCs can be derived from distant (systemic) sources, including the bone marrow, adipose tissue, and possibly other organs. The signals mediating MSC mobilization to blood, survival in blood, and the attraction of MSCs to tumors are not known.

Figure 2. The physical parameters and cell surface molecules of MSCs cooperate to induce active homing of MSCs to tumors

Endothelial cells are green; MSCs are blue; and tumor cells are pink. Although the mechanisms of MSC homing are poorly understood, they likely involve partially overlapping steps of deceleration in the blood flow (which may be partially physical – here depicted as bulging endothelial cells), rolling, adhesion, transmigration through the endothelium, and migration into surrounding tissues. The possible molecular determinants are indicated. The elucidation of the MSC homing mechanism to tumors will facilitate the development of drugs for inhibition of this process (endogenous MSCs), or for understanding how ex vivo cultured MSCs can be engineered to be used as effective and specific drug delivery vehicles.

Figure 3. MSC differentiation within tumors

MSCs have been found to differentiate to (a) osteoblasts (red), adipocytes (yellow), or other cell types; (b) pericytes; (c) cancer stem cell niche cells; and (d) tumor associated fibroblasts. The precise function of each of these cell types remains to be determined. Each step may be targeted for inhibition by therapies, based on their function in promoting or inhibiting tumor progression or initiation.

Figure 4. MSC tumor progression promoting functions

(a) MSCs may promote tumor cell proliferation and inhibit cell death. (b) MSCs may promote angiogenesis within tumors. (c) MSCs may inhibit some immune functions, while promoting others. (d) MSCs may promote tumor metastasis, possibly at multiple steps (from initial dissemination to formation of novel niches in distal tissues). (e) MSCs may regulate cancer stem cell self-renewal and differentiation.

Figure 5. Combinatorial cancer therapy and detection using engineered exogenous MSCs

(a) Cell surface chemistry using biotin-streptavidin conjugation or enzymatic modification can be used to attach multiple ligands (yellow and green) on the MSC surface. Different combinations of these ligands can be used to combinatorally target MSCs to specific tissues in the body (e.g., tumor). (b) Genetic engineering techniques may be used to express anti-tumorigenic molecules including interferons (IFN) and prodrug converting enzymes. (c) Drugs (small orange circles) can be encapsulated in micro or nanoparticles (large red circles), which in turn can be engulfed by MSCs. (d) Drug release from MSCs will cause tumor cell death. (e) Spatiotemporal micronenvironment sensing (SMS): Tumor microenvironment, intercellular signaling, and tumor progression may be imaged via molecular probes such as surface-conjugated FRET aptamers.