Oncometabolome and MALDI-MSI in Upper GI Carcinomas - Chemosensitivity in Esophageal Carcinoma.

Introduction Esophageal cancer is one of the most common types of cancer worldwide. However, the incidence of esophageal cancer varies significantly by region, with higher rates observed in some countries such as Japan and South Korea. Tumors detected early have a better prognosis than advanced tumors. The 5-year survival rates for patients with esophageal cancer vary depending on the stage from 90% for localized tumours to only 5% in advanced stages (> T2, N+), whereby "patient" always refers to both genders. As the majority of patients are mainly diagnosed at a locally advanced stage, multimodal treatment is currently recommended in most cases before curative resection. The success of the systemic therapy, which in Germany is usually carried out as chemotherapy alone with the FLOT protocol or as radiochemotherapy with the CROSS protocol, is assessed postoperatively in the final histological evaluation by means of the degree of regression. According to Becker, the resulting degrees of regression are graded into stages 1 to 3, with grade 1 reflecting almost complete regression after systemic therapy and grade 3 indicating a postoperative residual tumor with > 50 % vital tumor cells and thus a poor response to neoadjuvant therapy.

The reason for favorable versus a poor response in esophageal adenocarcinoma cannot lie solely in the patients clinical characteristics and genetic subtype. Rather, the metabolic phenotype plays a decisive role. However, the metabolic phenotype of esophageal adenocarcinomas with different regression grade has not yet been sufficiently researched.

Rationale The oncological outcome of the esophageal adenocarcinoma depends on various factors, including in particular tumor size, tumor metabolism and the growth pattern of the primary tumor and infiltrated lymph nodes. An advanced tumor size is associated with an increased risk of local and systemic metastases and a poorer prognosis. At the same time, tumor size is associated with altered metabolic activity, particularly glycolysis. Tumor biology, which can be mapped using metabolomics, also plays an important role in the prognosis and treatment of these cancers. The expression of biomarkers such as HER2 and PD-L1 can also be of decisive importance both in the choice of therapy and in predicting the response to a particular treatment. However, locoregional growth, response to chemotherapy and tumor size also play a significant role in patient survival.

The tumor microenvironemt (TME), is frequently observed in esophageal carcinoma to induce cell proliferation and thus hardens the surrounding tissue and restricts blood flow to the tumor, which in turn reduces the effectiveness of chemotherapy and radiotherapy. Another key feature of tumor cell metabolism is the ability to extract nutrients from a frequently nutrient-poor microenvironment and use these nutrients to meet the demands of growth and proliferation. In this way, the TME gradually forms, encompassing cancer cells, the cytokine environment, the extracellular matrix, subgroups of fibroblasts and immune cells. Within this complex network of cancer cells and cancer-related metabolic products, the pro-tumorigenic environment plays a central role in stimulating tumor angiogenesis and promoting its invasiveness and metastatic potential. Certain tumor-associated metabolites are linked to aggressive cancer phenotypes, facilitated angiogenesis, promoted mutagenesis, and suppression of the immune system. However, the migration of cancer-related metabolites from the tumor itself and its microenvironment into the systemic bloodstream can be detected and quantified using state-of-the-art clinical mass spectrometry. Therefore, abnormal amino acid and phospholipid metabolism in various cancers plays a diverse and crucial role, and the potential impact of metabolic control and regulation within the tumor microenvironment is gaining increasing importance.

While metabolomics is already implemented in basic research, early detection, diagnosis, and therapy for metabolic diseases such as type 2 diabetes mellitus, there is currently a high demand for the application of targeted metabolomics in oncological diseases. In various entities, it has been observed that the metabolome within the TME harbors a significant alteration in amino acid and phospholipid metabolism. From a metabolic perspective, current investigations focus particularly on an increase in membrane-bound polar phospholipids and a decrease in apolar phospholipids and phosphate¬idylserines to characterize, for example, the response to chemotherapy.