More candidate genes imply how complexity to eliminate the evil

Worldwide, colorectal cancer (CRC) is the most lethal and prevalent malignancy and was responsible for nearly 881 000 cancer-related deaths in 2018.¹ Despite the pathophysiologic mechanism of CRC being more complex than beyond thought, recent advances in the treatment of CRC provided more strategies, but the results were not satisfactory. In this issue, a study from Lin et al, reported that five STAT3-downstream genes were over-expressed in CRC-derived tumorspheres, including BHLHE40, ATF3, ERRFI1, ITPKA, and S100A14. As expected, the authors found that knockdown of STAT3 diminished the cell viability in HT29 cells in vitro since STAT3 was believed to involve in the initiation of cancer stemness property and progression. Therefore, these STAT3-downstream genes may contribute to cell proliferation and survival.

For the treatment of CRC, it is more complex. Ideally, the treatment goal is to remove the tumor as completely as possible, either at primary or metastatic sites, which mostly requires surgery. However, surgical intervention is limited to patients with resectable lesions and tolerant to surgery. Otherwise, tumor shrinkage and down-stage by radiotherapy and/or chemotherapy as neoadjuvant or adjuvant treatment are the leading options in the junction of surgically unresectable and intolerable patients. In recent decades, research studies demonstrated combination chemotherapy including FOLFOX (5-FU + OX), FOXFIRI (5-FU + IRI), XELOX or CAPOX (CAP + OX), and CAPIRI (CAP + OX) in CRC patients had prolonged their overall survival (OS) up to 20 months, especially those with metastases.² Nonetheless, the response results of chemotherapy in survival were not satisfactory, therapy targeting the CRC initiation, progression, and migration pathways became approaches to reinforce chemotherapy. In 1995, the first monoclonal antibody targeting EGFR-mediated pathways, named cetuximab, targeted to EGFR with convincing preclinical data were announced.³ Combinations of cetuximab with other existing chemotherapies also displayed promising results. The phase III CRYSTAL trial found that cetuximab plus FOLFIRI had better progression control (8.9 vs 8 months, hazard ratio [HR] 0.85; P = .048) than FOLFIRI alone.³ Another landmark trials, AVF2107 trial based on antiangiogenic therapy by a humanized IgG monoclonal antibody targeted to VEGF-A, named bevacizumab, for CRC improved both progression-free survival (PFS) and OS in metastatic CRC (RR: 44% vs 34.8%; OS: 20.3 vs 15.6 months; HR: 0.66, P < .001; PFS: 10.6 vs 6.2 months; HR: 0.54; P < .001).⁵ Several agents targeting various pathways such as BRAF inhibitor/MEK inhibitor, human epidermal growth factor receptor (HER)2 inhibitor, hepatocyte growth factor (HGF), and the receptor tyrosine kinase known as mesenchymal-epithelial transition factor (c-MET or MET) were undergone further investigation. Recent newly-developed immune checkpoint therapy such as pembrolizumab, one of PD-1 blockers, in KEYNOTE-016 study was found a better response in CRC patients with mismatch repair deficient (dMMR) by pembrolizumab treatment (response rate of 40% and a 20-week PFS of 78%).⁶ In CheckMate-142 trial, another monoclonal PD-1 antibody, nivolumab, showed a promising result that achieved disease control for at least 12 weeks, with an objective overall response rate of 31.1%, and 1-year PFS and OS values of 50.4% and 73.4%, respectively.⁷ Although new agents provide more strategies in CRC treatment, the results can be improved by more studies. According to the present study by Lin et al in this issue, five STAT3-downstream genes, including BHLHE40, ATF3, ERRFI1, ITPKA, and S100A14, can be candidate targeting genes for CRC treatment in further researches.

Interestingly, the gut microbiota was found as an indispensable factor for CRC treatment. Gut microbiota affected responses and adverse reactions of immune checkpoint blockade.⁸ Several strains of bacteria were related to the drug response, such as Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.⁹ More evidence revealed that gut microbiota is closely related to carcinogenesis and tumor progression of CRC.¹⁰ Although no disease-specific organism responsible for CRC has been identified so far, patients with CRC have shown dysbiosis and Firmicutes, and Bacteroidetes were more predominant in CRC.¹¹ Moreover, Firmicutes, Fusobacteria, and Bacteroidetes were enriched in CRC patients compared with control and benign adenoma.¹² Disease onset and progression of CRC related to specific bacteria, such as Fusobacterium nucleatum, and several metabolites have been reported.¹³ As the exploration of H. pylori and its relationship with gastric cancer, it might be possible to discover some CRC-related pathogens and diminish colorectal cancer in decades.

According to the latest report from Health Promotion Administration (HPA), Ministry of Health and Welfare (MOHW) of Taiwan, colorectal cancer (CRC) remained the second most common malignancy with incidence rate of 53.73 per 100 thousand people and the third leading cause of cancer-related deaths. In the past few years, the news that some celebrities died of colorectal cancer has made the public pay more attention to colorectal cancer. Since a nationwide screening program by biennially fecal immunochemical test (FIT) was launched to individuals aged 50 to 75 in Taiwan from 2004,¹⁴ the incidence rate of CRC has initially risen as more colorectal cancers were diagnosed at the beginning of the implementation due to increasing number of screening. However, it has reached a plateau and even had a downward trend in the past 3 years. Besides, FIT screening attributed to actual reduction of CRC mortality was 62% (relative rate for the screened group vs the unscreened group, 0.38; 95% confidence interval, 0.35-0.42) with a maximum follow-up of 6 years. The 21.4% coverage of the population receiving FIT led to a significant 10% reduction in CRC mortality (relative rate, 0.90; 95% confidence interval, 0.84-0.95).¹⁵ As far there is no absolute solution for a complete cure of CRC except early detection and prevention.

The present paper by Lin et al, about gene profiling expressions of HCT116- and HT29-derived cancer stem-like cells (CSCs), demonstrated STAT3-mediated genes overexpressing in CSCs. They also showed Napabucasin (BBI608), an inhibitor targeting to STAT3, inhibited tumorspheres formation. The evidences indicated STAT3 and its down-stream genes BHLHE40, ATF3, ERRFI1, ITPKA, and S100A14, which may play crucial roles in maintaining the cancer stem-like tumorspheres. More studies targeting these genes may provide further informative help to control CRC.

The author declares no conflict of interest.