Figure 2: BAFF in cancer cachexia interplay. Outer arrows indicate well-described hallmarks of cancer cachexia. Cancer → inflammation: many types of cancer cells express cytokines that induce inflammation [119]. Inflammation → cancer: tumors often manifest on inflammatory background that supports transition of cells to malignant clones (e.g., hepatocellular carcinoma or PDAC as cited in the text). Cancer → cachexia: tumor tissue directly participates in the development of cancer cachexia by production of tumor specific factors like PIF and LMF [120, 121]. Cachexia → cancer: cachexia in cancer patients remains a significant cause of morbidity and mortality in cancer treatment [122]. Inflammation → cachexia: proinflammatory cytokines induce cachexia by increased catabolism with altered insulin sensitivity [119]. Inner arrows indicate established (solid line) and putative (dashed line) role of BAFF in pathophysiology of cancer cachexia. Cancer → BAFF: increased expression and serum levels of BAFF were demonstrated in many types of hematological and solid tumors making BAFF a possible new biomarker in malignancies. BAFF → cancer: BAFF has been found to augment manifestation of lymphoma and the formation of epithelial-mesenchymal transitions and pancreatic intraepithelial neoplasias. These events precede PDAC. (1) A TNF-independent role of BAFF in the pathophysiology of lymphomas was demonstrated in BAFF-Tg TNF−/− mice. More than 35% of BAFF-Tg TNF−/− mice had occurrence of various types of lymphomas within 1 year [123]. (2) BAFF-induced alteration of the epithelial-mesenchymal transition- (EMT-) related genes that support precancerous formation of pancreatic intraepithelial neoplasias and PDAC was confirmed on BAFF-R overexpressing cell clones [91]. Inflammation → BAFF: BAFF is produced by several proinflammatory cells. BAFF → inflammation: BAFF induces expression of proinflammatory cytokines by activation of NF-κB [124]. BAFF → cachexia: BAFF induces insulin resistance [40, 117] which has been associated with cancer cachexia [116, 118].