Potential role of transmembrane 9 superfamily member 1 as a biomarker in urothelial cancer

Abstract

Bladder cancer is a urological tumor with high rates of recurrence despite recent advances in novel therapies. Many proteins involved in the molecular mechanisms are currently an enigma, especially the transmembrane 9 superfamily member 1 which has an unclear function. Wei et al published the function and mechanism of this protein, and showed that it could participate in the proliferation, migration and invasion of tumor cells in bladder cancer, therefore treatments directed against this protein may be beneficial in avoiding this condition.

Key Words: Bladder cancer; Transmembrane 9 superfamily member 1; Biomarker; Urothelial cancer; Protein

Core Tip: The overexpression of transmembrane 9 superfamily member 1 promotes cells into the gap 2/mitosis phase of the cell cycle and has a role in autophagy and immune-mediated mechanisms, therefore, the potential inhibition of transmembrane 9 superfamily member 1 or related pathways could result in antitumoral activity, providing a new target in the treatment of patients with bladder cancer.

INTRODUCTION

Urothelial cancer therapy is a rapidly evolving field, with several approaches that have proven superiority over previous standards in all stages of the disease, from the earliest stages, such as localized non-muscle invasive bladder carcinoma, to more advanced stages, such as muscle-invasive bladder cancer (MIBC), or metastatic disease.

Nevertheless, the main factors that guide most of the treatment-related decisions are still based on clinical and pathological factors, that, at best, are just prognostic, without any clear predictive value that could help individualize therapy in patients with urothelial tumors. For example, in localized MIBC, the current standard approach is cisplatin-based neoadjuvant chemotherapy (NAC) followed by surgery, with or without adjuvant immunotherapy. This strategy has consistently shown an absolute benefit in overall survival that ranges from 5% to 8%[1]. However, whether or not to give NAC to an individual patient is mainly based on the stage of the disease (T2-T4, N0-N1, M0), and the expected tolerability of the patient to a cisplatin-based chemotherapy combination[2]. Patients who achieve most benefit from this approach are those with a pathologic complete response in the cystectomy specimen, accounting from 30% to 45% of the whole population that receive NAC. From a different point of view, about 55%-70% of patients that receive NAC get little or no benefit from this approach, are exposed to toxic chemotherapy, and surgery, as a potentially curative treatment, is delayed without getting any benefit from NAC. This is only an example of how the lack of predictive biomarkers impacts the treatment landscape, and how the need for precision medicine in this setting is unmet.

ROLE OF TRANSMEMBRANE 9 SUPERFAMILY MEMBER 1

In a World Journal of Clinical Oncology article, Wei et al[3] published very interesting work on the potential role of transmembrane 9 superfamily member 1 (TM9SF1) in urothelial neoplasms, concluding that it may enhance growth, migration and invasion of bladder cancer cells, both by promoting their entry into the phase gap 2/mitosis G2/M phase of the cell cycle, and by probably having a role in autophagy and immune-mediated mechanisms. There is previous evidence that TM9SF1 is a differentially expressed gene among several histologic types of urothelial tumors; however, the role of TM9SF1 in bladder cancer is unclear, and the cellular processes TM9SF1 are involved in remain essentially unknown[4]. Other works suggest that TM9SF1 could be involved in the autophagy process, with TM9SF1 overexpression inducing autophagy, and TM9SF1 expression knockdown by RNA interference hampers starvation-induced authophagy[5]. This oncogenic role of TM9SF1 has already been confirmed in other neoplasms, such as cervical cancer[6], esophageal cancer[7], and gastric tumors[8], being potentially correlated with aggressiveness and prognosis.

This work proves the role of TM9SF1 overexpression in reducing the number of tumor cells in the G1 phase of the cell cycle, therefore prompting them to enter the G2/M phase and start mitosis; also, TM9SF1 silencing blocks cells in the G1 phase and prevents them from entering the DNA replication phase, thereby inhibiting bladder cancer cell proliferation. Therefore, potential inhibition of TM9SF1 or related pathways could result in antitumoral activity. TM9SF1 also seems to have a role in reducing anti-tumor immune responses, and this work also confirms the prominent role of TM9SF1 in autophagy. Furthermore, knockdown of TM9SF1 expression by RNA interference could hamper starvation-induced autophagy[5].

CONCLUSION

Due to the available results, further research involving TM9SF1 and its overexpression in bladder cancer is warranted. If confirmed in larger studies, involving patients in different stages of the disease, the role of TM9SF1 as a potential prognostic and predictive biomarker for guiding treatment-decision making could be of major interest, as the development of biomarkers in this tumor is an urgent and unmet medical need.