Cancer-related CD15/FUT4 overexpression decreases benefit to agents targeting EGFR or VEGF acting as a novel RAF-MEK-ERK kinase downstream regulator in metastatic colorectal cancer

Abstract

BackgroundCancer-related immune antigens in the tumor microenvironment could represent an obstacle to agents targeting EGFR “cetuximab” or VEGF “bevacizumab” in metastatic colorectal cancer (mCRC) patients.MethodsInfiltrating immune cells into tumor tissues, cancer-related expression of immune antigens (CD3, CD8, CD68, CD73, MPO, CD15/FUT4) from 102 mCRC patients receiving first-line Cetuximab or Bevacizumab plus chemotherapy were assessed by immunohistochemistry and validated in an independent tissue microarrays of 140 patients. Genome-wide expression profiles from 436 patients and 60 colon cancer cell lines were investigated using bioinformatics analysis. In vitro kinase assays of target genes activated by chemokines or growth factors were performed.ResultsHere, we report that cancer-related CD15/FUT4 is overexpressed in most of mCRCs patients (43 %) and associates with lower intratumoral CD3+ and CD8+ T cells, higher systemic inflammation (NLR at diagnosis >5) and poorer outcomes, in terms of response and progression-free survival than those CD15/FUT4-low or negative ones (adjusted hazard ratio (HR) = 2.92; 95 % CI = 1.86–4.41; P < 0.001). Overexpression of CD15/FUT4 is induced through RAF-MEK-ERK kinase cascade, suppressed by MEK inhibitors and exhibits a close connection with constitutive oncogenic signalling pathways that respond to ERBB3 or FGFR4 activation (P < 0.001). CD15/FUT4-high expressing colon cancer cells with primary resistance to cetuximab or bevacizumab are significantly more sensitive to MEK inhibitors than CD15/FUT4-low counterparts.ConclusionCancer-related CD15/FUT4 overexpression participates in cetuximab or bevacizumab mechanisms of resistance in mCRC patients. CD15/FUT4 as a potential target of the antitumor immune response requires further evaluation in clinical studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0225-7) contains supplementary material, which is available to authorized users.

CRISPR/Cas9 Screens Reveal Requirements for Host Cell Sulfation and Fucosylation in Bacterial Type III Secretion System-Mediated Cytotoxicity

“…Despite their diverse products, each of the transduced FUTs rendered the corresponding CHO cell lines susceptible to T3SS2 killing (Figure 5G). Thus, terminal fucosylation in a variety of forms and contexts can mediate susceptibility to T3SS2 killing and the specific identification of FUT4 in the screen likely reflects the major contribution of this FUT to fucosylation in HT-29 cells (Giordano et al, 2015). …”

Role of fucosyltransferase IV in the migration and invasion of human melanoma cells

“…All these are high mannose-type structures. Another 16 Nglycans were upregulated in C8161 cells (peaks 2, 5, 6,9,11,15,16,17,19,21,25,26,30,31,35, and 37; A375P/ C8161 relative intensity ratio of >0.5; Table 2) and are fucosylated or nonfucosylated neutral oligosaccharides. In order to further gauge different fucosylation levels between the two cell lines, N-glycan composition profiling corresponding to fucosylated oligosaccharides was evaluated.…”

“…12 FUT4 catalyzes the α-1,3 fucose linkage in Lewis x and Lewis y structures, which is associated with tumor proliferation, invasion, and metastasis. [12][13][14] Increased FUT4 levels have been reported in multiple cancers, including acute myeloid leukemia, 15 colon, 16 and gastric and lung cancers. 17,18 In addition, increased FUT4 expression has been shown to promote cell proliferation and metastasis while preventing apoptosis.…”

Role of CD15 expression in dysplastic and neoplastic tissue of the bile duct – a potential novel tool for differential diagnosis of indeterminate biliary stricture

“…The prognostic relevance of CD15 molecules is still discussed, as high expression of sCD15 could be correlated with poor outcome with various forms of cancer, including CCA . Furthermore, overexpression of CD15 has been shown to participate in resistance mechanisms to targeted therapy in colon cancer . However, the prognostic relevance of CD15 status of CCA has not been described so far.…”

“…[17][18][19] Furthermore, overexpression of CD15 has been shown to participate in resistance mechanisms to targeted therapy in colon cancer. 20 However, the prognostic relevance of CD15 status of CCA has not been described so far.…”