Biomarker discovery for renal cancer stem cells

Abstract

Characterised by high intra‐ and inter‐tumor heterogeneity, metastatic renal cell carcinoma (RCC) is resistant to chemo‐ and radiotherapy. Therefore, the development of new prognostic and diagnostic markers for RCC patients is needed. Cancer stem cells (CSCs) are a small population of neoplastic cells within a tumor which present characteristics reminiscent of normal stem cells. CSCs are characterised by unlimited cell division, maintenance of the stem cell pool (self‐renewal), and capability to give rise to all cell types within a tumor; and contribute to metastasis in vivo (tumourigenicity), treatment resistance and recurrence. So far, many studies have tried to establish unique biomarkers to identify CSC populations in RCC. At the same time, different approaches have been developed with the aim to isolate CSCs. Consequently, several markers were found to be specifically expressed in CSCs and cancer stem‐like cells derived from RCC such as CD105, ALDH1, OCT4, CD133, and CXCR4. However, the contribution of genetic and epigenetic mechanisms, and tumor microenvironment, to cellular plasticity have made the discovery of unique biomarkers a very difficult task. In fact, contrasting results regarding the applicability of such markers to the isolation of renal CSCs have been reported in the literature. Therefore, a better understanding of the mechanism underlying CSC may help dissecting tumor heterogeneity and drug treatment efficiency.

Alternative splice variants of DCLK1 mark cancer stem cells, promote self‐renewal and drug‐resistance, and can be targeted to inhibit tumorigenesis in kidney cancer

“…c ). This finding may be significant as the proximal tubule is thought to be the cell of origin for ccRCCs, and vasculature supports progression in renal malignancy. Comparatively, normal tissue adjacent to malignancy shows little DCLK1 expression in blood vessels and tubules, and decreased expression overall.…”

Claspin overexpression is associated with high‐grade histology and poor prognosis in renal cell carcinoma

“…Cancer stem cells are thought to be responsible for recurrence or distant metastasis and for chemotherapy and radiotherapy resistance in many malignancies . Cancer stem cells are frequently identified by surface protein markers such as CD44, CD105, CD133, ALDH1, and CXCR4 in RCC . Among these surface markers, CD44 is the most frequently reported, and a positive correlation has been suggested with aggressive behavior in RCC .…”

“…25 Cancer stem cells are frequently identified by surface protein markers such as CD44, CD105, CD133, ALDH1, and CXCR4 in RCC. 9,26,27 Among these surface markers, CD44 is the most frequently reported, and a positive correlation has been suggested with aggressive behavior in RCC. 28,29 In fact, many studies have shown that CD44 expression was reported to significantly correlate with high nuclear grade, vein invasion, recurrence, and poor prognosis, and it has been suggested to be a useful prognostic marker.…”

Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients

“…The selected surface markers have been previously identified as stem cell markers in the kidney (i.e. CD24, CD29, CD133) 15 , cancer stem cell markers in other malignancies (CD24, CD29, Epcam, CD44, MET, CD90, ALDH1A1 activity) [16][17][18][19][20][21] , and in the kidney (CD133, CD24, CD105, CXCR4) 8,9,15,22 . FACS revealed a distinct population of CXCR4 + MET + cells in patient's tumor which could be further sorted into CD44 + and CD44 − cells ( Fig.…”