Exploring cell competition for the prevention and therapy of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is characterized by the development of cancer in the esophageal squamous epithelium through a step-by-step accumulation of genetic, epigenetic, and histopathological alterations. Recent studies have demonstrated that cancer-associated gene mutations exist in histologically normal or precancerous clones of the human esophageal epithelium. However, only a small proportion of such mutant clones will develop ESCC, and most ESCC patients develop only one cancer. This suggests that most of these mutant clones are kept in a histologically normal state by neighboring cells with higher competitive fitness. When some of the mutant cells evade cell competition, they become "super-competitors" and develop into clinical cancer. It is known that human ESCC is composed of a heterogeneous population of cancer cells that interact with and influence their environment and neighbors. During cancer therapy, these cancer cells not only respond to therapeutic agents but also compete with each other. Therefore, competition between ESCC cells within the same ESCC tumor is a constantly dynamic process. However, it remains challenging to fine-tune the competitive fitness of various clones for therapeutic benefits. In this review, we will explore the role of cell competition in carcinogenesis, cancer prevention, and therapy, using NRF2, NOTCH pathway, and TP53 as examples. We believe that cell competition is a research area with promising targets for clinical translation. Manipulating cell competition may help improve the prevention and therapy of ESCC.

Abuse Liability, Anti-Nociceptive, and Discriminative Stimulus Properties of IBNtxA.

IBNtxA (3-iodobenzoyl naltrexamine) is a novel µ-opioid receptor (MOR) agonist which is structurally related to the MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, resulting in anti-nociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants, but further evaluation of its in vivo pharmacological profile is necessary. The purpose of this study was to independently verify the antinociceptive properties of IBNtxA and to examine more completely the rewarding properties and discriminative stimulus effects of IBNtxA, allowing broader assessment of IBNtxA as a candidate for further medications development. A dose of 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot-plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and vehicle, the κ-agonist U-50488 fully substituted for IBNtxA. MOR agonist morphine, δ-agonist SNC162, NOP agonist SCH 221510, and MOR/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. A dose of 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal. Overall, IBNtxA has a complicated opioid receptor pharmacology in vivo. These results indicate that IBNtxA produces potent anti-nociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.