Biomaterials to suppress cancer stem cells and disrupt their tumoral niche
Graphical abstract
Introduction
Conventional cancer treatment is based on two premises: first, that cancer cells are a homogeneous population that displays a distinct phenotype as compared to healthy cells, and that medicines can take advantage of these differences to eliminate the disease (Clevers, 2011). The second premise is that the tumoral niche is a clinically advantageous feature, at least for nanomedicine-based therapies, since its enhances permeability to macromolecules and nanocarriers and promotes their accumulation in the tumor (Schätzlein, 2006). Nowadays, there is growing evidence demonstrating that these two premises are incorrect or at least incomplete.
Tumor cell heterogeneity is now a widely accepted feature of cancer and can be discussed at the genetic and developmental levels, being both of these tightly connected. At the genetic level, tumor cells present intrinsic genetic variability, which results in several cancer subclones that evolve following Darwinian processes in an attempt to adapt towards the environment. This process leads to an enrichment of cells presenting advantageous mutations and more aggressive phenotype (Greaves and Maley, 2012). At the developmental level, it has been confirmed that tumor initiation and relapse is driven by a selected tumor cell subpopulation that has high resistance towards conventional therapies and that takes advantage of stem cell-specific features (Farrar, 2009, Marotta and Polyak, 2009). Antitumorals are designed to target rapidly cycling cells such as those from the tumor bulk, but will spare the quiescent (but deadly) cancer stem cells (CSCs) that will generate tumor relapse and metastasis (Clevers, 2011).
Tumor niche (TN) refers to the microenvironment that interacts with tumor cells and regulates their fate. TN has been revealed as a critical barrier for cancer treatment and it is analyzed in this manuscript through four different features: the vascular niche, the inflammatory and immunosuppresive niche, the hypoxic niche and the extracellular matrix, all of which are closely related among themselves, with the CSC phenotype (Fig. 1). The tumor microenvironment was mostly seen as an advantage in the past, since it enhances the permeability and retention of the nano-sized drugs in the tumor (i.e. the EPR effect). However, tumor vasculature is highly irregular and could be tight in some regions, while being leaky in others. This irregular growth of tumor vasculature also generates non-functional branches, leading to poorly irrigated regions that cannot be easily accessed with chemotherapy (Jain, 2005). Besides, the accumulation of stroma in the tumor and the high intratumoral pressure also prevent drug transport to the inner regions. A recent survey of the literature has indicated that only a 0.7% of the nanocarrier dose is delivered to solid tumors (Wilhelm et al., 2016), a results that suggests the failure of the overall concept of passive targeting as it is understood nowadays.
Besides its barrier effect to drug delivery, the tumor niche also provides important signaling, often related to the cancer stem cell phenotype, that promotes tumor spreading and protection. CSCs and their niche have been recognized as critical features of cancer progression in the last years, and are currently in the focus of intense programs for drug development. Indeed, some prototypes have been developed to the stage of clinical implementation or are in advanced clinical trials (Fig. 2). Most of the programs, however, are still focusing on separate aspects of CSCs and the TN, and as it will be illustrated in this review, those features are tightly interconnected (Fig. 1) and might not be effectively addressed separately.
The field of biomaterials and drug delivery, mostly in tissue engineering, has focused on pulsing important cell signaling routes, particularly those related to stem cell development, and understanding and mimicking the biological substrate (the “niche”). Concretely, scaffolds and other tissue engineering devices are frequently used to: (i) induce stem differentiation (Prabhakaran et al., 2009), (ii) deliver cell-cycle modulators (Nayab et al., 2007), (iii) modulate the inflammatory niche (Lisignoli et al., 2006), (iv) modulate tissue vasculature (Stegemann and Nerem, 2003) and (v) induce extracellular matrix remodeling (Schneider et al., 2010). This spectrum of biological activity fits perfectly the requirements of a new generation of antitumorals capable of modulating CSCs and their niche.
The objective of this review is to analyze the properties and implications of the CSC phenotype and the TN, and to cover the main therapies designed to address these characteristics, focusing on the potential role of biomaterial-based technologies (i.e. implants, nanomedicines, etc.) in such therapies.
Section snippets
Cancer stem cells
Cancer stem cells (CSCs) have been defined as a cell subpopulation in the tumor bulk that possesses stem cell capacities. CSCs may be derived from adult stem cells or progenitor cells, but also from terminally differentiated cells that undergo epigenetic changes (Marotta and Polyak, 2009, Hermann et al., 2010). In any case, malignant cells take advantage of stem cell-specific signaling to drive tumor development.
CSCs were isolated for the first time in the 1990′s in acute myeloid leukemia, and
Aberrant vasculature
The formation of abnormal blood and lymphatic vessels is one of the critical hallmarks of solid tumors, which is driven by the secretion of high concentrations of angiogenic factors by the tumor cells. On one hand, the role of this abnormal vasculature is the nutrition and oxygenation of the tumor, but it also has a regulatory role in the secretion of growth factors and cytokines that spur tumor growth. Tumor-induced angiogenesis results in different vessels from those in normal vasculature as
Outlook and conclusions
While there have been considerable advances in oncology over the last decades, several types of cancer still present very low survival rates. Many of these are cancers where a tumor initiating cell subpopulation with stem cell-like properties has been reported. Despite the existence of this population, therapies that where under clinical development in the last decade failed to recognize the importance of cancer stem cells (CSCs), while they also neglected the importance of the main traits of
Conflict of interest
The authors declare no conflicts of interest.
Authors contribution
CGM and NC performed the bibliographic search. MGF designed the paper outline. All authors contributed to data analysis, writing and revision of the manuscript.
Acknowledgments
The authors acknowledge funding from Fundación BBVA, Proyectos de Investigación en Biomedicina (2014-PO0110) and Ministerio de Economía y Competitividad (SAF2014-58189-R, FEDER Funds).
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