Targeting tumor microenvironment to curb chemoresistance via novel drug delivery strategies

ABSTRACT

Introduction: Tumor is a heterogeneous mass of malignant cells co-existing with non-malignant cells. This co-existence evolves from the initial developmental stages of the tumor and is one of the hallmarks of cancer providing a protumorigenic niche known as tumor microenvironment (TME). Proliferation, invasiveness, metastatic potential and maintenance of stemness through cross-talk between tumors and its stroma forms the basis of TME.

Areas covered: The article highlights the developmental phases of a tumor from dysplasia to the formation of clinically detectable tumors. The authors discuss the mechanistic stages involved in the formation of TME and its contribution in tumor outgrowth and chemoresistance. The authors have reviewed various approaches for targeting TME and its hallmarks along with their advantages and pitfalls. The authors also highlight cancer stem cells (CSCs) that are resistant to chemotherapeutics and thus a primary reason for tumor recurrence thereby, posing a challenge for the oncologists.

Expert opinion: Recent understanding of the cellular and molecular mechanisms involved in acquired chemoresistance has enabled scientists to target the tumor niche and TME and modulate and/or disrupt this communication leading to the transformation from a tumor-supportive niche environment to a tumor-non-supporting environment and give synergistic results towards an effective management of cancer.

KEYWORDS:

• Tumor microenvironment (TME)
• drug delivery approaches
• chemoresistance
• immune infiltrates
• cancer stem cells (CSCs)

Article highlights

• The outcome of a standard chemotherapeutic regimen is non-predictive because of the involvement of the non-malignant cells i.e. the tumor microenvironment (TME). This TME modulates the chemotherapy rendering it less effective.

• TME is responsible for the development of chemoresistance through a well-defined mechanistic process and is actively involved in potentiating tumor outgrowth, metastasis and chemoresistance.

• These processes usually express several traits unique to the tumors and its surrounding stroma. Iincrease in TSA/TAA, upregulation of cytokines and chemokines, accumulation of immunosuppressive infiltrates can be targeted to disrupt the TME and thus, the tumor mass.

• Synergism though the co-delivery of chemotherapeutics, TASCs modifying and TASCs triggered drug release to internalize drug in the tumor cells will disrupt the pro-tumor niche and yield significant tumor inhibition.

• However, clinical translation of these investigational concepts needs to be warranted through further studies for effective tumor management.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.