Liver cancer is among the leading global healthcare issues associated with high morbidity and mortality. Liver cancer consists of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and several other rare tumors. Progression has been witnessed in understanding the interactions between etiological as well as environmental factors and the host in the development of liver cancers. However, the pathogenesis remains poorly understood, hampering the design of rational strategies aiding in preventing liver cancers. Accumulating evidence demonstrates that aberrant activation of the Wnt/β-catenin signaling pathway plays an important role in the initiation and progression of HCC, CCA, and HB. Targeting Wnt/β-catenin signaling potentiates a novel avenue for liver cancer treatment, which may benefit from the development of numerous small-molecule inhibitors and biologic agents in this field. In this review, we discuss the interaction between various etiological factors and components of Wnt/β-catenin signaling early in the precancerous lesion and the acquired mechanisms to further enhance Wnt/β-catenin signaling to promote robust cancer formation at later stages. Additionally, we shed light on current relevant inhibitors tested in liver cancers and provide future perspectives for preclinical and clinical liver cancer studies.

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAF^V600E colorectal cancer (mCRC^BRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRC^BRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43^mutated versus MSS-RNF43^wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRC^BRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

Mutations of the adenomatous polyposis coli ( APC ) gene predispose individuals to familial adenomatous polyposis (FAP), characterized by multiple tumours in the large intestine. Most mouse models heterozygous for truncating mutant Apc alleles mimic FAP, however, the intestinal tumours occur mainly in the small intestine. To model large intestinal tumours, we generated a new conditional Apc -mutant allele, Apc^15lox , with exon 15 flanked by loxP sites. Similar survival of Apc^1638N/15lox and Apc^1638N/+ mice indicated that the normal function of Apc was not impaired by the loxP sites. Deletion of exon 15, encoding nearly all functional Apc domains and containing the polyadenylation signal, resulted in a mutant allele expressing low levels of a 74 kDa truncated Apc protein. Germ line Cre-mediated deletion of exon 15 resulted in Apc^Δ15/+ mice, showing a severe Apc^Min/+ -like phenotype characterized by multiple tumours in the small intestine and early lethality. In contrast, conditional Cre-mediated deletion of exon 15 specifically directed to the epithelia of distal small and large intestine of Fabpl Cre ; Apc^15lox/+ mice led to longer survival and to tumours that developed predominantly in the large intestine, mimicking human FAP-associated colorectal cancer and sporadic colorectal cancer. We conclude that the Fabpl Cre ; Apc^15lox/+ mouse should be an attractive model for studies on prevention and treatment of colorectal cancer.

Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types. Identifying and targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the enrichment of LGR5 expressing cells, a well-recognized stem cell marker, in mouse liver tumors, and the upregulation of LGR5 expression in human hepatocellular carcinoma. Isolated LGR5 expressing cells from mouse liver tumors are superior in initiating organoids and forming tumors upon engraftment, featuring candidate TICs. These cells are resistant to conventional treatment including sorafenib and 5-FU. Importantly, LGR5 lineage ablation significantly inhibits organoid initiation and tumor growth. The combination of LGR5 ablation with 5-FU, but not sorafenib, further augments the therapeutic efficacy in vivo. Thus, we have identified the LGR5⁺ compartment as an important TIC population, representing a viable therapeutic target for combating liver cancer.

Whereas aberrant activation of canonical Wnt/β-catenin signaling underlies the majority of colorectal cancer cases, the contribution of non-canonical Wnt signaling is unclear. As enhanced expression of the most extensively studied non-canonical Wnt ligand WNT5A is observed in various diseases including colon cancer, WNT5A is gaining attention nowadays. Numerous in vitro studies suggest modulating capacities of WNT5A on proliferation, differentiation, migration and invasion, affecting tumor and non-mutant cells. However, a possible contribution of WNT5A to colorectal cancer remains to be elucidated. We have analyzed WNT5A expression in colorectal cancer profiling data sets, altered WNT5A expression in colon cancer cells and used our inducible Wnt5a transgenic mouse model to gain more insight into the role of WNT5A in intestinal cancer. We observed that increased WNT5A expression is associated with poor prognosis of colorectal cancer patients. WNT5A knockdown in human colon cancer cells caused reduced directional migration, deregulated focal adhesion site formation and reduced invasion, whereas Wnt5a administration promoted the directional migration of colon cancer cells. Despite these observed protumorigenic activities of WNT5A, the induction of Wnt5a expression in intestinal tumors of Apc 1638N mice was not sufficient to augment malignancy or metastasis by itself. In conclusion, WNT5A promotes adhesion sites to form in a focal fashion and promotes the directional migration and invasion of colon cancer cells. Although these activities appear insufficient by themselves to augment malignancy or metastasis in Apc 1638N mice, they might explain the poor colon cancer prognosis associated with enhanced WNT5A expression.