Tissue origins of cancer
Human beings and companion animals are complex, multicellular, eukaryotic organisms with a hierarchical organization of tissues that provide anatomic structure and specialized function.
All nucleated cells that make up bodily tissues of chordates are derived from one of three primary germ cell layers – the endoderm, the mesoderm, and the ectoderm – within the developing embryo. The endoderm serves as the origin of cells that form the epithelial component of visceral organs, including the lining of the gastrointestinal and respiratory tracts, as well as endocrine glands such as the thyroid and pancreas. The mesoderm forms tissues responsible for anatomic structure and function and includes skeletal muscle, bone, connective tissue, heart, and the urogenital system, while the ectoderm gives rise to the outer components of the body including skin and hair, as well as some parts of the central nervous system (Solnica-Krezel & Sepich, 2012; Tam et al., 2003).Given that cancer is a disease of self-tissues, it is not surprising that the origins of cancer can also be traced back to specific embryonic cell layers, with human beings and companion animals exhibiting some divergence in the predominant tissue origins for the most commonly occurring cancers. In humans, most cancers (~80%) arise from the endoderm germ layer, which constitutes the epithelial linings and glandular tissues of the body. Cancers arising from the endoderm and most cancers of the ectoderm are classified as epithelial malignancies such as adenomas or carcinomas and are distinguished based on their respective biologic behaviors.Malignant epithelial tumors, termed carcinomas, account for more than 80% of the cancer-related deaths in the USA, and specifically as a result of metastatic disease. The most common carcinomas of endodermal tissues arise from the epithelial linings of the colon, lung, breast, and prostate; however, the most and least biologically aggressive carcinomas are of pancreas and thyroid origin, respectively (Ryan et al., 2014; Schneider & Chen, 2013; Thota et al., 2014).
Carcinomas can be broadly segregated into two categories based on the major function of epithelia. Epithelial cells that provide a protective and sealed anatomic barrier can give rise to squamous cell carcinomas, while epithelial cells with specialized secretory activities can develop into adenocarcinomas. While epithelial malignancies are less common in companion animals, some prominent problematic tumors include oral squamous cell carcinoma in felines and urothelial carcinomas in canines (Bilgic et al., 2015; Knapp et al., 2019).The mesoderm serves as the predominant germ cell layer, which gives rise to nonepithelial malignancies in human beings and companion animals and can be broadly divided into two distinct categories. The first group of mesoderm-derived cancers develop from mesenchymal cell lineages and are termed sarcomas. In comparison with epithelial malignancies, sarcomas in humans constitute only a small percentage (1%) of adult tumors; however, they contribute to a substantive fraction (>20%) of tumors diagnosed in the pediatric population, primarily affecting the musculoskeletal system (osteosarcoma, Ewing’s sarcoma) (Burningham et al., 2012). For companion animals, the percentage of cancers classified as mesenchymal in origin is approximately equal to tumors derived from the endoderm germ cell layer (Dobson et al., 2002). Connective tissue cells, including fibroblasts, adipocytes, osteoblasts, myoblasts, and endothelial cells, can give rise to the development of sarcomas. The mesoderm also serves as the origin of hematopoietic tissues, and the second category of cancers arising from this embryonic germ cell layer includes a diverse group of ‘liquid’ tumor histologies collectively referred to as hematopoietic malignancies. In companion animals, hematopoietic malignancies, such as diffuse, large B-cell lymphoma, make up the lion’s share of ‘liquid’ cancers, with lymphoid leukemia and multiple myeloma comprising a smaller fraction of cancer types (Atherton & Mason, 2022).
Nervous tissues develop from the gastrulation and transplantation of the ectodermal germ cell layer with subsequent formation of the neuroectoderm, which can give rise to cancers of the central and peripheral nervous system including astrocytomas, neuroblastomas, schwannomas, oligodendrogliomas, and medulloblastomas (Pytel & Lukas, 2009). In addition to the three germ cell layers, migratory and multipotent cells derived from the neural crest, including melanocytes and neurosecretory cells, can malignantly transform to develop cancers including melanoma, small-cell lung carcinoma, and functional adrenal gland tumors. As mentioned previously, the emergence of comparative oncology has afforded unique opportunities to study companion animal tumors that are believed to have shared biology (Oh & Cho, 2023). The National Cancer Institute has identified six tumor types of comparative interest, being diffuse large B-cell lymphoma, mammary gland carcinoma, astrocytoma, osteosarcoma, urothelial carcinoma, and oral malignant melanoma.