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WT mice showed more severe infiltration of inflammatory cells in the brain, accom-
panied by higher activation of microglia cells around the hippocampus, than prnp
null mice, thus indicating that PrP play some roles in induction of inflammation
[ 85 ]. Due to PrP response to both TNFα, a pro-inflammatory cytokine, and TGFß,
an anti-inflammatory cytokine, it was assumed that PrP may play dual roles in
inflammation reaction. Working with the PrP-deficient mouse model, Liu et al.
showed that PrP participates in pro-inflammatory responses by upregulating cyto-
kines such as TNFα, IL-1ß, IL-6, and NOS2 during acute stage to eliminate
LPS. However, PrP plays a role in anti-inflammatory reaction by increasing expres-
sion of cytokines such as IL-10, Arg1, and Mrc1 during tissue-repairing stage [ 86 ].
Previously, we reported that about 13% of patients in PanIN-3 stage showed posi-
tive staining for PrP [ 46 ], and Zhang et al. [ 87 ] reported that PrP immune-reaction-
positive specimens increased from 15–42 to 95% when comparing oral normal
mucosa, leukoplakia, and squamous cell carcinoma tissues, suggesting a positive
correlation from normal, inflammation transition to cancer. Since in some cases PrP
favors inflammation response and chronic inflammation may cause tumor, expres-
sion of PrP in precancerous stage may be a key factor initiating tumor.
13.5 Remarks and Perspectives
The notion that PrP contributes to tumorigenesis was an unanticipated one since PrP
null mice develop apparent normally without obvious phenotype. Those PrP null
mice strongly suggest that PrP is not an essential protein during mice development.
However, the concept that PrP is a garbage protein present in mammals is not sup-
ported by its conservation in evolution, its location in lipid raft, and its complex
posttranslational modifications during protein biogenesis. On the contrary, PrP is a
multifunctional protein, and many of its functions can be substituted by other pro-
teins. In considering that most cancer patients die from cancer cell metastasis and
multidrug resistance, it is natural to target any proteins expressed in cancer cells to
fulfill these two functions. Based on the evidences that PrP facilitates cell adhesion
and migration and protects cells against apoptosis, it is not surprising that expres-
sion of PrP is a biomarker for poor prognosis in some cancer types. Besides metas-
tasis and drug resistance, angiogenesis is another important factor for cancer cell
development. In fact, PrP was implicated in developmental angiogenesis although
no detailed mechanism was provided [ 88 ]. It is well known that VEGFR2 is impor-
tant for tumor angiogenesis; by searching the physiological function of unglycosyl-
ated PrP, we identified an interaction between unglycosylated PrP and VEGFR2 in
CHO cells. This result strongly suggests that PrP, maybe behaving as Dpl, partici-
pates in tumor angiogenesis [ 89 ]. By binding to VEGFR2 in tumor endothelial cells,
Dpl stimulates VEGFR2 signaling and enhances tumor vascularization. Blocking
X. Yang et al.