Cancer Biology Research

Specific internal signals trigger events in the cell cycle Progress through the cell cycle depends on the activities of cyclin-dependent kinases, or CDKs. We know that a protein kinase is an enzyme that catalyzes the transfer of a phosphate group from ATP to a target protein; this phosphate transfer is called phosphorylation. A particular CDK controls the G1-to-S transition, which is a control point in the cell cycle called the restriction point (R). Other CDKs control other parts of the cell cycle. CDKs are not enzymatically active as protein kinases unless they are bound to another class of protein, the activators called cyclins. The binding of its cyclin—an example of allosteric regulation—activates the CDK by altering its shape and exposing its active site to substrates. The cyclin–CDK that controls passage from G1 to S phase is not the only such complex involved in regulating the eukaryotic cell cycle. There are different cyclin–CDK complexes, composed of particular cyclins and their associated CDKs, that act at different stages of the cycle. The details of how these complexes form and function vary among eukaryotic organisms, but we will focus here on the complexes found in mammalian cells. As an example, let’s take a closer look at the cyclin–CDK complex that controls the G1-to-S transition. Binding of a cyclin changes the three-dimensional structure of an inactive CDK, making it an active protein kinase. Each cyclin–CDK complex phosphorylates a specific target protein in the cell cycle.

In this blog post, we’ll explore how the HE4 test works, its clinical applications, benefits, and limitations, and answer some of the most common questions about this innovative diagnostic tool.

Lynch Syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is a genetic condition that increases the risk of various cancers, especially colorectal cancer. This disorder is caused by mutations in DNA mismatch repair genes like MLH1, MSH2, MSH6, and PMS2, leading to a higher likelihood of DNA errors during cell division. This blog post will explore Lynch Syndrome, its genetic basis, associated cancer risks, and strategies for prevention and management.

Lactate in Tumor Inflammation and Angiogenesis Lactic acid promotes the angiogenesis of tumor cells by affecting endothelial cells. The entry of lactic acid into the tissue stroma by tumor cells can be facilitated by endothelial cells via MCT1. This process inhibits the degradation of HIF-1α in non-hypoxic endothelial cells. As a result, there is a significant up-regulation of endothelial cell production of VEGF and fibroblast growth factor (FGF), thus promoting angiogenesis. In addition to promoting neovascularization, lactic acid plays a role in tumor development that is often associated with inflammatory responses. Th17 cells in the tumor microenvironment gradually increase and promote the secretion of the cytokine IL-17 during tumor development. IL-17 can up-regulate the production of various pro-inflammatory cytokines and pro-angiogenic factors, further promoting tumor development. Source: Liu H, Pan M, Liu M, Zeng L, Li Y, Huang Z, Guo C and Wang H (2024) Lactate: a rising star in tumors and inflammation. Front. Immunol. 15:1496390.

Lactate and Immune Escape in Tumors Cancer is a complex disease characterized by genetic mutations, cell apoptosis, and uncontrolled cell growth. A key mechanism behind tumor progression is "immune escape," where tumors evade immune surveillance. Tumor metabolism plays a critical role in this process, with tumor cells consuming glucose under hypoxic conditions and producing lactate, which alters the tumor microenvironment (TME). Immunosuppressive Effects of Lactate Lactate accumulation in the TME exerts immunosuppressive effects by influencing immune cell functions. High lactate levels inhibit the cytotoxicity and motility of T-cells and natural killer (NK) cells, leading to immune dysfunction. It directly affects NK cell lysis capacity and induces their apoptosis. In T-cells, lactate regulates polarization, inhibits Th1 cells, promotes Treg differentiation, and sustains cancer progression through the TLR8/miR21 axis. Impairment of Immune Surveillance Lactate impairs cytotoxic CD8+ T-cell infiltration and function, weakening immune surveillance against tumors. Additionally, it inhibits the production of type I interferon (IFN-γ) in both T-cells and NK cells, limiting immune activation and reducing the body's defense against cancer. Macrophage Polarization and Immune Escape Lactate also affects tumor-associated macrophages (TAMs), which play a role in tumor growth and immune modulation. Lactate promotes the polarization of macrophages from the cytotoxic M1 phenotype to the tumor-promoting M2 phenotype, suppressing immune responses in the TME. It also increases the expression of arginase 1 (Arg1) and vascular endothelial growth factor (VEGF) in TAMs, further supporting tumor growth. Infiltration of Suppressor Cells Lactate promotes immune escape by increasing the infiltration of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), which hinder NK cell function and contribute to the immunosuppressive TME. This process plays a significant role in suppressing the natural immune response against tumor development. Source: Liu H, Pan M, Liu M, Zeng L, Li Y, Huang Z, Guo C and Wang H (2024) Lactate: a rising star in tumors and inflammation. Front. Immunol. 15:1496390. #lactate #cancerresearch #TumorMicroenvironment #cancerimmunology #cancerbiologyresearch

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The potential of Circulating Tumor Cells (CTCs) Circulating Tumor Cells (CTCs) are cancer cells that detach from primary or metastatic tumors and enter the bloodstream. They serve as a key indicator of cancer metastasis and progression, as their presence in blood can reflect the spread of cancer beyond the original site. The analysis of CTCs holds significant potential in the early detection of cancer, offering a less invasive alternative to traditional biopsy methods. This approach can provide real-time insights into tumor characteristics and genetic mutations, aiding in personalized treatment plans. CTC analysis is also being explored for monitoring treatment response and detecting minimal residual disease. By tracking the number and characteristics of CTCs over time, doctors can assess how well a therapy is working and whether the cancer is likely to relapse. In addition, CTCs can offer valuable information on tumor heterogeneity, as they often exhibit genetic diversity. This helps in understanding how cancer evolves and adapts, providing critical insights into how tumors may resist treatment or metastasize.

Production of Lactate in the Tumor Microenvironment (TME) 👇 The tumor microenvironment (TME) in cancer is immunosuppressive and promotes tumor growth, while the microenvironment in chronic inflammatory diseases is proinflammatory and anti-tumor. Despite these differences, both environments share similar metabolic conditions, such as hypoxia, elevated lactate, and reduced nutrients. The TME consists of mesenchymal and immune cells, the extracellular matrix (ECM), and various metabolites and signaling molecules, all of which play a role in regulating cancer-related processes like energy metabolism, growth, angiogenesis, invasion, metastasis, and immune evasion. This environment leads to an imbalance of normal cells, producing factors that support tumor growth. A key feature of the TME is lactate accumulation due to altered metabolism in tumor cells, particularly through glycolysis and glutamine pathways. Lactate, co-transported with protons, acidifies the TME, which hinders immune cell function, especially cytotoxic T cells and NK cells. Additionally, lactate promotes the development of immunosuppressive cells, further weakening the immune response against tumors. Source: Liu H, Pan M, Liu M, Zeng L, Li Y, Huang Z, Guo C and Wang H (2024) Lactate: a rising star in tumors and inflammation. Front. Immunol. 15:1496390.

Evidence of Tumor Monoclonality👇 📎(A) In normal plasma, immunoglobulin (Ig) molecules, such as antibodies, display a heterogeneous distribution when subjected to gel electrophoresis (illustrated as a polyclonal Ig population at the top of the left channel). This heterogeneity reflects the involvement of a diverse array of plasma cells in antibody production. In contrast, multiple myeloma is characterized by the emergence of a single antibody species, known as an M-spike, produced by a clonal population of antibody-secreting tumor cells. 📎(B) An unusual chromosomal translocation (indicated by an arrow) involves the exchange of segments between two nonhomologous chromosomes—depicted as a red chromosome and a yellow chromosome (only one product of the translocation is shown). This translocation creates a distinctive “signature” that sets apart the affected cell from neighboring karyotypically normal cells (top row). As all cancer cells in a resulting tumor exhibit the identical, rare translocation (bottom row), this supports the idea that they originate from a common progenitor in which the translocation first occurred. Credit: Robert A. Weinberg, Robert A Weinberg - The biology of cancer (2014, Garland Science) #tumor #cancer #cancerbiology #cancerbiologyresearch