Colorectal Cancer Subtypes: Developmental Origin and Microenvironmental Regulation

Colorectal cancer (CRC) is not a single disease; it can be classified into biologically and clinically distinct subgroups that can influence prognosis and response to therapy. The biological conformity within each subtype suggests common underlying drivers and holds promise for the design of subtype-specific treatments. Each CRC subtype presents a complex system of cancer and nontransformed stromal cells. Both the presence of microenvironmental components and their influence on epithelial tumor cells impact subtype affiliation. CRC subtypes are being modeled in vitro using cell line panels for subtype-specific screening approaches, yet, more sophisticated model systems are needed to recapitulate the interplay with the tumor microenvironment. Cancer is a heterogeneous disease and many cancer types do not represent a single entity, but are composed of biologically and clinically diverse subtypes. The subtype affiliation can influence prognosis and response to therapy. Recently, a multicenter colorectal cancer (CRC) subtyping consortium introduced a consensus molecular classification system for CRC. This will be of great benefit for future basic and clinical research since it enables uniform categorization of CRC specimens across different institutes and studies. The biological conformity observed within each consensus molecular subtype (CMS) holds promise for the design of subtype-specific treatment regimens. Herein, we review the CMSs of CRC with a focus on how multiple parameters, such as the origin, developmental route, and microenvironmental regulation shape distinct subtypes. Cancer is a heterogeneous disease and many cancer types do not represent a single entity, but are composed of biologically and clinically diverse subtypes. The subtype affiliation can influence prognosis and response to therapy. Recently, a multicenter colorectal cancer (CRC) subtyping consortium introduced a consensus molecular classification system for CRC. This will be of great benefit for future basic and clinical research since it enables uniform categorization of CRC specimens across different institutes and studies. The biological conformity observed within each consensus molecular subtype (CMS) holds promise for the design of subtype-specific treatment regimens. Herein, we review the CMSs of CRC with a focus on how multiple parameters, such as the origin, developmental route, and microenvironmental regulation shape distinct subtypes. a cell is aneuploid if it carries an abnormal number of chromosomes (i.e., more or less than 46 chromosomes in a human cell). cell that is the target of the first mutational hit(s) that may lead to malignant transformation. monoclonal antibody that binds to the epidermal growth factor receptor and inhibits its activation and thus downstream signaling. Cetuximab has been approved for the treatment of metastatic CRC without KRAS mutation. the CpG island methylator phenotype is defined as hypermethylation of CpG islands, which are frequently located in promoter regions of genes. Therefore, CIMP can lead to epigenetic silencing of tumor suppressor genes such as CDKN2A. chromosomal instability is present in approximately two-thirds of CRC cases and refers to tumors with aneuploid chromosome sets carrying multiple structural and numerical aberrations. The causes of CIN are not well defined. the clustered regularly interspaced short palindromic repeat-CRISPR-associated nuclease system is a prokaryotic immune system that protects bacteria from invading foreign genetic sequences. The components of this system can be used for genome editing, that is, for knocking out specific genes or for replacing a given genetic sequence with the sequence of interest. cancer cells undergoing the epithelial–mesenchymal transition program lose epithelial characteristics, such as polarity and cell–cell adhesion, and gain mesenchymal features that allow them to leave the primary site and disseminate to distant organs. hereditary nonpolyposis colorectal cancer syndrome, also known as Lynch syndrome, is a cancer syndrome associated with the increased risk of developing colorectal cancer, among others, due to the inheritance of mutations inactivating components of the DNA mismatch repair system. microsatellite instability; MSI+ tumors are characterized by a near-diploid genome and instability in the form of insertions and deletions in microsatellite regions. MSI is caused by a defective mismatch repair system in the sporadic form most frequently due to inactivation of one of its main components, MLH1, by promoter hypermethylation. a cell is multipotent if it possesses the capability to differentiate into multiple, yet limited, cell types. mathematical decomposition of gene-expression data of tumor samples based on predefined signatures. This approach aims to digitally separate gene expression from normal, malignant, and stromal components within one tumor to identify cell type-specific gene expression and pathway activation.