The Clinical Impact of Cancer Stem Cells

Abstract

Patients with cancer can go though many stages in their disease, including diagnosis, recurrence, metastasis, and treatment failure. Cancer stem cells (CSCs) are a subgroup of cells within tumors that may explain the mechanism by which tumors recur and progress. CSCs can both self-renew and produce progenitor cells of more differentiated cancer cells as well as heterogeneously demonstrate resistance and the abilities to migrate and metastasize. These "stemness" characteristics are often the result of dysregulation of one or more pathways, which can be detected by various biomarkers. Although there has been considerable laboratory research conducted on CSCs, its relevance to the practicing oncologist may seem questionable. We sought to determine the clinical impact of CSCs on patients. A systematic literature search was conducted to identify analyses containing survival information based on the expression of known CSC biomarkers in any cancer. Overall, 234 survival analyses were identified, of which 82% reported that high expression of CSC biomarker(s) resulted in poor overall survival and/or disease-free survival compared with low or no expression of the biomarker. Elevated stemness biomarker levels were also associated with decreased tumor differentiation, altered TNM stage, and increased metastasis. This analysis would suggest that CSCs have a clinical impact on patients and that practicing oncologists need to start considering incorporating CSC-targeting therapies into their patients' treatment regimens. IMPLICATIONS FOR PRACTICE: Cancer stem cells (CSCs) may occur at any stage of cancer and are implicated in the occurrence of resistance, recurrence, and metastasis. A systematic literature analysis has shown that the presence of CSCs, identified via the upregulation of stemness pathway biomarkers, results in reduced survival across all cancers studied. Several CSC-targeting agents are currently approved, and several others are in clinical trials. Future treatment regimens will likely include CSC-targeting agents to enable the elimination of these holdouts to current therapies.

Keywords: Biomarker; Cancer stem cells; Clinical impact; Recurrence; Stem cell state; Stemness; Survival.

Figure 1

Stages of cancer diagnoses. Patient and oncologist encounter multiple types of diagnoses throughout the patient journey. Cancer stem cells may be present at any of these stages.

Figure 2

Clonal evolution model and cancer stem cell model of tumor growth (adapted from [4, 5]).

Figure 3

Key pathways identified as resulting in stemness characteristics when dysregulated 10, 11, 12, 13, 14, 15, 16.Abbreviations: JAK, Janus kinase; STAT, signal transducer and activator of transcription.

Figure 4

The presence of CSCs can have multiple outcomes for patients. CSCs can maintain themselves through self‐renewal, as well as differentiate. Activated stemness pathways can result in resistance to different therapies, allowing CSCs to re‐establish the tumor. Acquisition of migratory and invasive properties seen in epithelial–mesenchymal transitions coupled with tumor‐initiating capabilities enable tumors to metastasize.Abbreviation: CSC, cancer stem cell.

Figure 5

Clinical evidence reporting that stemness biomarkers are associated with poor survival in cancer. Published evidence of increased biomarker expression being associated with decreased overall survival is summarized under each cancer type [S1–S157]. See supplemetary material for analyses details and citations.