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.

Small Cell Carcinoma of the Rectum-An Unexpected Diagnosis: Current Treatment Options for a Rare and Aggressive Entity.

Rectal small cell carcinoma is a rare and aggressive cancer subtype for which a consensus of optimal treatment has not yet been reached. This cancer presents a difficult surgical problem, and thus, the mainstay of treatment tends to mirror that of small cell carcinoma of the lung (chemotherapy, radiation therapy, and immune modulators). This brief report highlights current treatment options available for this rare and difficult entity. There is a significant need for large-center clinical trials and prospective studies to help determine the best treatment regimen to effectively care for patients with small cell carcinoma of the rectum.

Identification and Treatment of SMARCA4 Deficient Poorly Differentiated Gastric Carcinoma.

Loss of expression of the SMARCA4 gene, a subunit of the SWI/SNF complex, has been historically associated with thoracic sarcomas. This loss of expression is extremely rare in gastric cancers, and its role in gastrointestinal tract carcinomas has not been fully elucidated. We report a case of a 73-year-old male with poorly differentiated, SMARCA4-deficient gastric cancer, showing that this immunophenotype is not limited to thoracic sarcomas or advanced-stage tumors. These tumors are often resistant to conventional FLOT chemotherapy and have poor prognoses, necessitating the need for early identification and alternative therapeutic approaches. New therapies such as EZH2 inhibitors and etoposide should be considered in cases where standard treatments are ineffective.

Next-Generation Sequencing in 305 Consecutive Patients: Clinical Outcomes and Management Changes.

PURPOSE: Next-generation sequencing (NGS) is increasingly used to identify actionable mutations for oncology treatment. We examined the results and use of NGS assays at our institution. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 305 consecutive patients who had NGS testing of tumor samples from March 2014 to April 2017. NGS was performed by FoundationOne. RESULTS: Of the 305 tissue samples sent to FoundationOne, 189 reports were potentially usable. Of these reports, 76 (40.21%) demonstrated an aberration targetable by on-label therapies and 126 (66.67%) by off-label therapies, and 170 (89.94%) revealed actionable aberrations via all potential avenues, including clinical trials; 21 of these 189 potentially usable reports (11.1%) yielded a change in management, including use of on-label therapies (n = 7), use of off-label therapies (n = 6), enrollment in a clinical trial (n = 6), and discontinuation of a medication with a predicted poor response (n = 3; one report was used twice). For the six patients with off-label use, median duration of treatment was 46 days and discontinued after death (n = 3) or progression (n = 3). CONCLUSION: Only a minority of NGS assay results (6.9% percent of all tests ordered and 11.1% of useable tests) resulted in a management change. A small minority of patients started off-label therapy on the basis of NSG assay results and overall had poor responses to off-label treatment. Although in theory NGS assays may improve oncologic outcomes, the results of our initial 305 patients showed low clinical utility.

Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells.

Microsomal triglyceride transfer protein (MTP), an endoplasmic reticulum (ER) chaperone that loads lipids onto apolipoprotein B, also regulates CD1d presentation of glycolipid antigens in the liver and intestine. We show MTP RNA and protein in antigen-presenting cells (APCs) by reverse transcription-polymerase chain reaction and by immunoblotting of mouse liver mononuclear cells and mouse and human B cell lines. Functional MTP, demonstrated by specific triglyceride transfer activity, is present in both mouse splenocytes and a CD1d-positive mouse NKT hybridoma. In a novel in vitro transfer assay, purified MTP directly transfers phospholipids, but not triglycerides, to recombinant CD1d. Chemical inhibition of MTP lipid transfer does not affect major histocompatibility complex class II presentation of ovalbumin, but considerably reduces CD1d-mediated presentation of alpha-galactosylceramide (alpha-galcer) and endogenous antigens in mouse splenic and bone marrow-derived dendritic cells (DCs), as well as in human APC lines and monocyte-derived DCs. Silencing MTP expression in the human monocyte line U937 affects CD1d function, as shown by diminished presentation of alpha-galcer. We propose that MTP acts upstream of the saposins and functions as an ER chaperone by loading endogenous lipids onto nascent CD1d. Furthermore, our studies suggest that a small molecule inhibitor could be used to modulate the activity of NKT cells.

CD1d function is regulated by microsomal triglyceride transfer protein.

CD1d is a major histocompatibility complex (MHC) class I-related molecule that functions in glycolipid antigen presentation to distinct subsets of T cells that express natural killer receptors and an invariant T-cell receptor-alpha chain (invariant NKT cells). The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins. Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B, associates with CD1d in hepatocytes. Hepatocytes from animals in which Mttp (the gene encoding MTP) has been conditionally deleted, and IECs in which Mttp gene products have been silenced, are unable to activate invariant NKT cells. Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis. These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo.