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Page 10 of 23 ALHulais et al. J Cancer Metastasis Treat 2019;5:3 I http://dx.doi.org/10.20517/2394-4722.2018.71

of ascitic tumor cells. This therapy has contributed greatly to the management of breast cancer patients
with malignant ascites and peritoneal carcinomatosis [115] . EPCAM is also expressed by almost all human
adenocarcinomas, retinoblastoma, hepatocellular and squamous cell carcinomas [116] .

[117]
EPCAM can be downregulated when cancer cells undergo EMT , during the dissemination of cancer cells
into other tissues. Hence, detecting cancer cells in blood as CTCs using EPCAM as a marker is likely to miss
the invasiveness/migration events of tumor cells. EPCAM is also expressed by the normal breast epithelial
cells, although its role in the homeostasis of normal breast tissue is unclear [118] . In the human kidney 2 (HK-
2) proximal cell line grown under hypoxic conditions, the activity of the EpCAM promoter is increased two
fold and in both HK-2 cells and primary kidney proximal cells, EPCAM protein expression is increased after
hypoxia and reoxygenation [119] . The widely distributed expression of EPCAM on most cancer cells makes
EPCAM unsuitable as a specific marker of CSCs.

CD271 (p75NTR)
CD271 was identified as the low-affinity nerve growth factor receptor (LNGFR), also known as the
p75 neurotrophin receptor (p75NTR) belonging to the tumor necrosis factor receptor and low-affinity
neurotrophin receptor superfamily and is a marker for cells of neural crest embryonic origin [120] . Previously,
human CD271 was shown to be expressed on cells of the peripheral and central nervous system and was
suggested to be involved in the survival, development as well as differentiation of neuronal cells [121] . CD271
or LNGFR is also found expressed on a wide range of other cell types including follicular dendritic cells,
mesenchymal stem cells (MSCs), astrocytes, Schwann cells, neural crest stem cells, oligodendrocytes,
sensory and autonomic neurons and mesenchymal cells [122] .

Studies have shown that CD271 (LNGFR) is a predominant biomarker expressed by MSCs isolated from the
bone marrow [123] . The fibroblastic colony forming units (CFU-F) in MSC populations could be established
+
-
only by the CD271 cell fractionation, whereas no CFU-F’s were obtained with the CD271 cell population.
CD271 is a highly specific marker expressed on the surface of freshly isolated bone marrow MSCs [124] . CD271
may not be a specific marker for all tissues, because as a marker it failed to isolate MSCs from umbilical cord
blood [123] .

CD271 was identified as a marker for the CSC population within human melanomas and its usefulness as
a melanoma CSC marker has been well documented [121] and was shown to be crucial for maintaining the
tumorigenicity and stem-like properties of melanoma cells [125] . CD271 has also been characterized as a stem
cell marker for a small percent of cells in oesophageal squamous cell carcinoma [126,127] and was associated
with CSCs [128] with high metastatic potential in CTCs from these cancer patients [129] . CD271 confers an
invasive and metastatic phenotype to head and neck squamous cell carcinomas through the upregulation of
the EMT transcription factor, Slug [130] which also promotes stemness. Thus, CD271 appears to be a marker of
CSCs across a range of cancer types.

CD271 overexpression on melanoma cells suppressed in vitro activation of melanoma specific cytotoxic T
lymphocytes [131] . Moreover, the expression levels of PD-L1 and CD271 on the melanoma cells were both
increased by IFNγ such that PD-L1 levels were related to those of CD271, and together with PD-L1 strongly
and additively suppressed melanoma specific CTL activation [131] . CD271 expression on melanoma cells has
also been linked to p53 activity, the DNA damage response and chemotherapeutic drug resistance as well as
migratory properties to form metastases [132-134] . The higher expression levels of CD271 may determine specific
properties of brain trophic metastatic melanoma cells [135,136] .

Hypoxia induced activation of the HIF-1α and HIF-2α as well as their target genes enhances tumorigenicity,
self-renewal, resistance to chemotherapeutic drugs and metastatic potential and is associated with increased