Over expression of B7-H1 (also named PDL-1 or CD 274) molecule in cancer has been linked to worse prognosis and resistance to anti-cancer therapies in several malignancies. In this review, we update on the expression of B7-H1 molecule in solid and hematological malignancies. We also describe the possible mechanisms by which this molecule inhibits/downregulates the immune response to cancer cells. Finally, we highlight current and future potential therapeutic strategies that can be further developed to target this molecule.
The anti-apoptotic BCL-2 proteins (BCL-2, BCL-XL, MCL-1, A1, BCL-W) counteract apoptotic signals emerging during development and under stress conditions, and are thus essential for the survival of every cell. While the "BCL-2 addiction" of different cell types is well described in mouse models, there is only limited information available on the role of different anti-apoptotic BCL-2 proteins in a given human cell type. Here we characterize the role of BCL-XL for survival and function of human hematopoietic cells, with the aim to predict hematological side effects of novel BCL-XL-inhibiting BH3-mimetics and to identify hematological malignancies potentially responsive to such inhibitors. Earlier clinical studies have shown that the combined BCL-2/BCL-XL/BCL-W inhibitor, Navitoclax (ABT-263) induces severe thrombocytopenia caused by direct platelet demise and counteracted by increased megakaryopoiesis. In contrast, murine studies have reported important contribution of BCL-XL to survival of late erythroid cells and megakaryocytes. Using lentiviral knockdown, we show that the roles of BCL-XL for human hematopoietic cells are much more pronounced than expected from murine data and clinical trials. Efficient genetic or chemical BCL-XL inhibition resulted in significant loss of human erythroid cells beginning from very early stages of erythropoiesis, and in a reduction of megakaryocytes. Most importantly, BCL-XL deficient human hematopoietic stem cells and multipotent progenitors were reduced in numbers, and they showed a severely impaired capacity to engraft in mice during xenotransplantation. BCL-XL deficiency was fully compensated by BCL-2 overexpression, however, loss of its antagonist BIM did not result in any rescue of human erythroid or stem and progenitor cells. We thus conclude that novel and specific BCL-XL inhibitors might be efficient to treat malignancies of erythroid or megakaryocytic origin, such as polycythemia vera, acute erythroid leukemia, essential thrombocytosis or acute megakaryocytic leukemia. At the same time, it can be expected that they will have more severe hematological side effects than Navitoclax.
Checkpoint kinase 1 (CHK1) is critical for S‐phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumor cells have developed a strong dependence on CHK1 for survival, and hence, this kinase has developed into a promising drug target. Chk1 deficiency in mice results in blastocyst death due to G2/M checkpoint failure showing that it is an essential gene and may be difficult to target therapeutically. Here, we show that chemical inhibition of CHK1 kills murine and human hematopoietic stem and progenitor cells (HSPCs) by the induction of BCL2‐regulated apoptosis. Cell death in HSPCs is independent of p53 but requires the BH3‐only proteins BIM, PUMA, and NOXA. Moreover, Chk1 is essential for definitive hematopoiesis in the embryo. Noteworthy, cell death inhibition in HSPCs cannot restore blood cell formation as HSPCs lacking CHK1 accumulate DNA damage and stop dividing. Moreover, conditional deletion of Chk1 in hematopoietic cells of adult mice selects for blood cells retaining CHK1, suggesting an essential role in maintaining functional hematopoiesis. Our findings establish a previously unrecognized role for CHK1 in establishing and maintaining hematopoiesis.
Gastric Cancer is a heterogeneous, multifactorial, aggressive disease that has been and still remains one of the most common causes of cancer-related death and a major public health issue worldwide. Currently, gastric cancer shows decreasing trends in its incidence and mortality in some geographic areas; however the disease still shows poor prognosis and remains difficult to cure. The prognosis for patients with gastric cancer depends on the stage at which the gastric cancer is detected, and complete excision of the cancer is the only proven curative option. However, recently the treatment of gastric cancer has been rapidly evolving with the emergence of new cytotoxic drugs and molecular targeted agents that show promising response rate and disease progression-free survival. Cancer prevention intervention such as screening to ensure early detection, population health education, anti-cancer knowledge popularization, identification and correction of unhealthy lifestyles has demonstrated to be effective; and improved treatment modalities can dramatically increase the poor prognosis for patients with gastric cancer. Demographic, ecological, environmental, culture, and genetic variables all contribute to the heterogeneity of gastric cancer; however, environmental risk factors play an important role throughout all the stages of the disease progression, management and surveillance. In this review, we address the role of important environmental risk factors in the onset of gastric cancer, and highlight the current treatments modalities and prevention measures for gastric cancer.
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