Cancer Stem Cells and the Tumor Microenvironment: Targeting the Critical Crosstalk through Nanocarrier Systems

Abstract

The physiological state of the tumor microenvironment (TME) plays a central role in cancer development due to multiple universal features that transcend heterogeneity and niche specifications, like promoting cancer progression and metastasis. As a result of their preponderant involvement in tumor growth and maintenance through several microsystemic alterations, including hypoxia, oxidative stress, and acidosis, TMEs make for ideal targets in both diagnostic and therapeutic ventures. Correspondingly, methodologies to target TMEs have been investigated this past decade as stratagems of significant potential in the genre of focused cancer treatment. Within targeted oncotherapy, nanomedical derivates-nanocarriers (NCs) especially-have emerged to present notable prospects in enhancing targeting specificity. Yet, one major issue in the application of NCs in microenvironmental directed therapy is that TMEs are too broad a spectrum of targeting possibilities for these carriers to be effectively employed. However, cancer stem cells (CSCs) might portend a solution to the above conundrum: aside from being quite heavily invested in tumorigenesis and therapeutic resistance, CSCs also show self-renewal and fluid clonogenic properties that often define specific TME niches. Further scrutiny of the relationship between CSCs and TMEs also points towards mechanisms that underly tumoral characteristics of metastasis, malignancy, and even resistance. This review summarizes recent advances in NC-enabled targeting of CSCs for more holistic strikes against TMEs and discusses both the current challenges that hinder the clinical application of these strategies as well as the avenues that can further CSC-targeting initiatives. Central role of CSCs in regulation of cellular components within the TME.

Keywords: Cancer Signaling; Cancer Stem Cells; Nanocarrier Targeting; Stemness Biomarkers; Stemness Pathways; Tumor Microenvironments.

Fig. 1

CTC interactions during the metastatic process. The above figure details the varying interactions that CTCs undergo, alongside their potential contributions towards the differentiation of the secondary TME from its pre-metastatic state. Out of these interactions, those with the immune aspects of the circulatory system seem to have the greatest impact on the TME’s characterizations between primary and secondary metastases [49]. (Created with BioRender)

Fig. 2

Principles of active and passive targeting for targeted drug delivery as well as stimuli-responsive drug release. a Passive targeting of CSCs, b Active targeting of CSCs, c Stimuli-responsive drug release. The above panel elaborates on the two main methodologies of targeted drug delivery to CSCs within tumors, namely active and passive targeting. It shows how passive targeting (a) is the basis over which active targeting (b) is a more specific overlayer. It approaches the tumor in the same manner as passive targeting, by taking advantage of the circulatory system and points of distorted endothelial lining near tumoral bases. But the actual biodistribution of the drug is intracytotic, made more direct to CSCs by engaging specifically with markers exclusive to particular CSC niches. This specificity is further enhanced by the mechanism of stimuli-responsive drug release (c), which caters to a spectrum of internal and external stimuli. (Created with BioRender)

Fig. 3

Model for multi-level targeting of CSCs via multiple or multifunctional ligands. a Targeting through surface biomarkers, b Targeting through ligand-interacting domain on the nuclear receptor, c Targeting through generic NP with multiple and multifunctional ligands, d Representation of multiple and multifunctional ligands. The above figure describes the basis through which prevalent NC-mediated targeting of CSCs via surface biomarkers (a), and genetic biomarkers (b), can be hypothetically merged into a model launching a multi-level attack (c). The model involves two ligand-orientation hypotheses, enabled through rounds of varying stimuli (d). The first is of a generic NP conjugated with two or more ligands that are respectively compatible with the external and internal markers being targeted. The functionalization of these ligands is a matter of steric organization and will differ in pertinence to the stem cell niche. The second model is of a multifunctional ligand that can be coaxed into different conformations compatible with specific levels of biomarkers, via rounds of distinct stimuli. (Created with BioRender)