The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission

ABSTRACT

Introduction: Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and is the second leading cause of cancer-related death in the United States. Despite advances in early detection, ~25% of patients are late stage, and treated patients have <12% chance of survival after five years. Tumor relapse and metastasis are the main causes of patient death. Cancer stem cells (CSCs) are a rare population of cancer cells characterized by properties of self-renewal, chemo- and radio-resistance, tumorigenicity, and high plasticity. These qualities make CSCs particularly important for metastasic seeding, DNA-damage resistance, and tumor repopulating.

Areas Covered: The following review article focuses on the role of CRC-SCs in tumor initiation, metastasis, drug resistance, and tumor relapse, as well as on potential therapeutic options for targeting CSCs.

Expert Opinion: Current studies are underway to better isolate and discriminate CSCs from normal stem cells and to produce CSC-targeted therapeutics. The intestinal receptor, guanylate cyclase C (GUCY2C) could potentially provide a unique therapeutic target for both non-stem cells and CSCs alike in colorectal cancer through immunotherapies. Indeed, immunotherapies targeting CSCs have the potential to break the treatment-recurrence cycle in the management of advanced malignancies.

KEYWORDS:

• Colorectal cancer
• cancer stem cell
• immunotherapy
• guanylate cyclase c

Article highlights

• Cancer stem cells (CSCs) are thought to drive therapeutic resistance, recurrence, and metastasis for all cancers.

• CSCs are a diverse collection of cell populations with high plasticity and variable marker expression, making their isolation and study challenging.

• Commonly used colorectal CSC markers also are expressed in normal intestinal stem cells, making detection of CSC populations in CRC patients difficult. L1CAM, a cell surface protein that is absent in intact intestinal tissue but is upregulated in MCSCs, could be a useful biomarker for CSC identification in later stage CRC patients and a possible indicator of prognosis.

• CSC-targeted therapies using anti-CSC and/or pro-differentiation drugs or immunotherapies are promising approaches to eliminate the treatment-recurrence-treatment cycle typical for many patients.

• While not found exclusively in CSCs, GUCY2C, a promising immunotherapy target in CRC reflecting anatomical and immunologic compartmentalization, may also be expressed and targeted in CRC-CSCs.

This box summarizes key points contained in the article.

Declaration of interest

SA Waldman is the Chair of the Scientific Advisory Board and member of the Board of Directors of, and AE Snook is a consultant for, Targeted Diagnostics and Therapeutics, Inc. which provided research funding that, in part, supported this work and has a license to commercialize inventions related to this work. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by the National Institutes of Health (R01 CA204881, R01 CA206026, and P30 CA56036), the Department of Defense Congressionally Directed Medical Research Program W81XWH-17-PRCRP-TTSA, and Targeted Diagnostic & Therapeutics, Inc. to SA Waldman. AE Snook received a DeGregorio Family Foundation award and was supported by the Defense Congressionally Directed Medical Research Programs (#W81XWH-17-1-0299, #W81XWH-19-1-0263, and #W81XWH-19-1-0067). SA Waldman and AE Snook also were supported by a grant from The Courtney Ann Diacont Memorial Foundation. M Crutcher was supported by an NIH institutional award T32 GM008562 for Postdoctoral Training in Clinical Pharmacology. SA Waldman is the Samuel M.V. Hamilton Professor of Thomas Jefferson University.