in RNA sequencing with higher precision and accuracy have further allowed researchers to determine transcriptomes of single cells. Such analyses are unveiling previously undiscovered mechanisms that contribute to cancer development (81), tumor heterogeneity (see Tumor Heterogeneity, p. 34), and treatment resistance (82). Protein Modifications Proteins are vital for normal cellular functions. The human proteome—the complete set of proteins made by humans— contains about 20,000 unique proteins. After being produced from mRNA, proteins can undergo additional modifications, providing great versatility and variability in their functions to meet cellular needs. Examining the proteome of cancer cells can unveil additional information about how cancer develops. For example, a recent study evaluated proteomes of nearly 1,000 cancer cell lines—tumor-derived cells that keep dividing and growing under certain conditions in the laboratory and are commonly used in medical research to understand molecular underpinnings of cancer development. Researchers identified common and unique cancer-related changes in levels of many proteins that were not detected at DNA or RNA levels (83). Modifications of proteins, also called posttranslational modifications (PTMs), are often necessary for normal cellular functions, such as responding to signals from outside the cell (84). Changes in normal PTMs of proteins can contribute to cancer (85). Identifying cancer-related PTM(s) has been central to developing effective anticancer therapeutics. Research has shown that many enzymes—specialized proteins that speed up chemical reactions in the body—that mediate PTMs exhibit altered function in cancer cells and are an attractive target for therapeutic development. This knowledge has led to the development and FDA approval of numerous molecularly targeted therapies that function by inhibiting the activity of such enzymes (74), thus expanding treatment options available to patients with cancer. Epigenetic Changes Epigenetic changes alter the structure of DNA without changing the DNA sequence. Epigenetic alterations occur when chemical marks are added to or removed from DNA, or when histone proteins undergo PTMs. Epigenetic changes may be acquired with age and/or exposure to environmental factors (e.g., air pollution) or behavioral factors (e.g., smoking) and psychosocial stressors (e.g., systemic racism), and may affect a person’s risk of cancer as well as be passed from parent to child. Epigenetic modifications regulate how and when genes are turned on or off. Specialized proteins add or remove unique epigenetic modifications to and from DNA and histones (86). In contrast to genetic mutations, most epigenetic changes are reversible. Cancer cells exhibit an altered epigenome—the complete set of all of the epigenetic changes in a cell. Because epigenetic changes are attractive targets for drug development, an area of active research is understanding how changes to the epigenome contribute to cancer development and how such changes can be targeted. Research over the years has led to development and approval of several anticancer therapeutics that function by modifying the cancer epigenome (87). Researchers are also leveraging the knowledge of the epigenome to categorize different types of cancer at a molecular level. For example, research has shown that mutations in proteins that add or remove epigenetic modifications are characteristics of glioma, a devastating type of brain cancer in children and adults (88). These findings can help identify new therapeutic targets in glioma and can accelerate the development of new drugs to treat this aggressive form of cancer. Systems That Enable Cancer Progression A hallmark of cancer is the ability of tumor cells to break away from the primary tissue and travel to other parts of the body. Systems that enable cancer to spread from the primary tissue to other organs of the body include the blood system, the lymphatic system, and the immune system (see Sidebar 8, p. 33). The Blood System The formation of new blood vessels, called angiogenesis, is a normal and essential process that occurs throughout life and is controlled by chemical signals in the body. The ability to promote angiogenesis toward and within a tumor is a hallmark of cancer. Tumor angiogenesis supplies high levels of oxygen and nutrients that are required to fuel rapid tumor growth. A recent analysis of 395 samples from patients with pancreatic cancer found that RBFOX2, a protein critical for RNA splicing, plays a crucial role in preventing metastatic transformation of earlystage pancreatic cancer, and may serve as a therapeutic target in pancreatic cancer (80). Exon Exon Exon Intron AACR Cancer Progress Report 2023 Understanding the Path to Cancer Development 32
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