Tumor cells can enter the lymphatic system in several ways, including adopting mechanical changes that facilitate cancer cell entry into the lymphatic system, and releasing certain molecules that help cancer cells move toward the lymphatic vessels (90). Once inside the lymphatic system, cancer cells acquire additional properties that make them more aggressive and facilitate their spread to other parts of the body (91). Ongoing research is focused on leveraging contributions of the lymphatic system in cancer growth and spread, including targeted delivery of anticancer therapy to lymph nodes as well as the development of drugs that block the migration of cancer cells toward lymphatic vessels (90). The Immune System The immune system is a complex network of cells, tissues, organs, and the substances they make that help the body fight infections and other diseases, including cancer (see Sidebar 8, p. 33, and Sidebar 38, p. 100). The immune system actively detects and eliminates abnormal or damaged cells from the body. However, because of the heterogeneous nature of the changes cancer cells acquire over time, some cancer cells obtain properties that help them evade the immune system. The properties of cancer cells that facilitate evasion from the immune system are one of the hallmarks of cancer. Extensive research over the last three decades has revealed some of the ways cancer cells evade the immune system (92). These include disruption of the cellular machinery that helps immune cells recognize damaged or abnormal cells; increasing levels of proteins in tumor cells that function as brakes on the immune system; and release of molecules that prevent the immune cells from becoming fully functional (93). Research has also shown that certain immune cells present in the tumor microenvironment (see Tumor Microenvironment, p. 35) can promote tumor growth (94). This issue of the AACR Cancer Progress Report includes a spotlight on advances in immunotherapy that highlights the tremendous progress that has been made in recent decades to harness the potential of the immune system to treat cancer (see Immunotherapy: Pushing the Frontier of Cancer Medicine, p. 99). Processes That Promote Cancer Growth and Metastasis Cancer metastasis refers to the spread of cancer cells from the tissue where they first originated to another part of the body. During metastasis, cancer cells break away from the original (primary) tumor, travel through the blood or lymph system, and form a new tumor in other organs or tissues of the body. Although the new, metastatic tumor acquires many additional alterations during the course of cancer development, it remains the same type of cancer as the primary tumor. For example, if prostate cancer spreads to the bone, the cancer cells in the bone are prostate cancer cells, not bone cancer cells. Patients with metastatic cancer have considerably lower 5-year survival rates than those with localized cancer (28). More than 90 percent of cancer-related deaths result from metastatic disease (95). Furthermore, chances of a cure are limited in patients with metastatic cancer, and thus researchers are continually uncovering additional complex processes that facilitate cancer metastasis. Tumor Heterogeneity During the course of disease, as cancer cells divide, they continue to acquire new alterations in their genomes, epigenomes, transcriptomes, and proteomes in various combinations and become more heterogeneous. Researchers use the term ‘tumor heterogeneity’ to describe the differences between cancer cells within a single tumor, the differences between tumors of the same type in different patients, or the differences between a primary (original) tumor and the metastatic tumor. Tumor heterogeneity plays a crucial role in cancer development and influences how cancer spreads, and how it responds to treatment. The heterogeneity of cancer cells in the primary tumor enables some tumor cells to acquire properties that facilitate their spread to other parts of the body. Tumor heterogeneity is also one of the major reasons why certain patients with cancer are resistant to treatments (96) (see Sidebar 35, p. 87). SINGLE-CELL SEQUENCING Sequencing of genomes, transcriptomes, epigenomes, and proteomes of individual cells allows researchers to understand the cellular and molecular features of cancer at the level of single cells, and helps discover aspects of cancer development, such as tumor heterogeneity, that may not be apparent from the averaged data obtained from sequencing all or part of the tumor (97). Proteome Epigenome Genome Transcriptome AACR Cancer Progress Report 2023 Understanding the Path to Cancer Development 34
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