Cancer Development and Causes PDF

Cancer Cells Global health issue High personal and financial burdens  Causes of Cancer Carcinogens: substances that cause cancer Identified by both laboratory studies and human population studies Most sporadic cases of cancer are the result of a complex mixture of exposure...

Cancer Cells Global health issue High personal and financial burdens  Causes of Cancer Carcinogens: substances that cause cancer Identified by both laboratory studies and human population studies Most sporadic cases of cancer are the result of a complex mixture of exposures to carcinogens Some cancers also have a genetic predisposition  The Ames Test Developed by scientist Bruce Ames in 1973 Culture Salmonella bacteria with a mutation that requires histidine for growth Exposed to a test chemical to see if they regained the ability to synthesize histidine, indicating a potential mutagenic activity and thus potential cancer risk What is cancer? Cancer: describes diseases in which tissues grow and spread unrestrained throughout the body, eventually choking off life Earliest documentation of cancer found on papyrus from ancient Egypt (1500 BCE) Hippocrates, “The Father of Medicine” Papyrus described tumors found in breast tissue that were managed using a heated tool called a “fire drill”, now known as a cauterization Cell Types Involved Cancers can originate in any organ Based on the cell type involved they are grouped into several different categories: Carcinomas: epithelial cells that cover external and internal body surfaces – 90% of all cancers, lung, breast, and colon are most common Sarcomas: develop from the cells of supporting tissues such as bone, cartilage, fat, connective tissue, and muscle Lymphoma & Leukemias: arise from cells of blood and lymphatic origin  Uncontrolled Cell Proliferation & Ability to Spread Abnormal tissue growth, the resulting mass is called a tumor (neoplasm) Tumor cells do not always divide more rapidly than normal cells, rather the issue is the balance between cell division and differentiation Cell Differentiation: process by which cells acquire specialized properties – generally associated with loss of the capacity to divide  Uncontrolled Cell Proliferation & Ability to Spread Benign tumors grow in a confined local area and is rarely dangerous In contrast, a malignant tumor can invade surrounding tissues, enter the bloodstream, and spread to Benign Tumor Malignant Tumor distant parts of the body Non-cancerous Cancerous Capsulated Non-capsulated Non-invasive Invasive Cancer, refers to any malignant Slow growing Often fast growing tumor Don’t metastasize Metastasize (spread) (spread) Cells have large, dark Cells are normal nuclei; may have abnormal Uncontrolled growth and ability to shape spread to distant locations is what makes cancer a life-threatening Cancer Cell Proliferation is Anchorage- Independent Normal cells don’t grow well in culture if they are suspended in a liquid medium When given a solid surface to anchor to they spread out and begin to proliferate Cancer cells grow well whether they are anchored or free floating In normal cells if Normal Cancer attachment to the ECM is prevented cells will often self-destruct (apoptosis), cancer cells circumvent this safeguard  Cancer Cells Lack Contact Inhibition In cell culture, normal cells divide and expand until the form a monolayer This is known as density- dependent inhibition of growth Cancer cells do not stop dividing when they reach a monolayer stage This could be in part due to alterations in E-cadherin Instead, they continue to divide and mediated signaling begin piling up on one another E-cadherin Mediated Regulation of Wnt Signaling E-cadherin is involved in several oncogenic pathways, including activation of Wnt signaling by nuclear localization of β-catenin β-catenin is the main nuclear effector of the Wnt signaling pathway β-catenin is also important in mediating functional interactions of cadherins Oncogenic: causing with cytoskeleton development of tumors Mendonsa, A.M., Na, TY. & Gumbiner, B.M. E-cadherin in contact inhibition and cancer. Oncogene 37, (2018). https://doi.org/10.1038/s41388-018-0304-2 E-cadherin Mediated Regulation of Wnt Signaling High levels of cadherin lead to sequestration of β-catenin thereby antagonizing Wnt signaling Cadherins have a superior binding affinity for β-catenin compared to TCF and outcompete TCF- β-catenin interactions Loss of Cadherins in the: Absence of Wnt = degradation Presence of Wnt = nuclear accumulation & Oncogenic: causing development of tumors target gene expression (cell proliferation & Mendonsa, A.M., Na, TY. & Gumbiner, B.M. E-cadherin in contact inhibition and cancer. Oncogene 37, apoptosis) (2018). https://doi.org/10.1038/s41388-018-0304-2  The Development of Cancer Fundamental Feature of cancer is tumor clonality – development of tumors from a single cells that begin to proliferate abnormally. The original progenitor cell does not initially acquire all of the characteristics of cancer cells. On the contrary, development of cancer is a multistep process involving: 1) Multiple mutations 2) Selection of cells with the capacity for proliferation, survival, invasion, and metastasis  The Development of Cancer The first step in the process, tumor initiation, is thought to be the result of a genetic alteration leading to abnormal proliferation of a single cell. This leads to outgrowth of a population of clonally derived tumor cells. Tumor progression continues as additional mutations occur. High degree of genetic instability in tumor cells contributes to clonal selection: mutations confer a selective advantage e.g., rapid growth, survival, invasion. Inactivation of Adenomatous Polyposis Coli (APC) 50 – 90% of colorectal cancers (CRC) are sporadic (only tumor cells have mutation) In sporadic CRCs, it has been proposed that sequential somatic mutations in: 1. APC (tumor suppressor inactivation) 2. Ras (oncogene activation) 3. p53 (tumor suppressor) result in progression from normal mucosa to carcinoma Colon carcinomas are a clear example Somatic mutations: changes to DNA that of tumor progression happen after conception to cells other than egg and sperm Inactivation of Adenomatous Polyposis Coli (APC) 50 – 90% of colorectal cancers (CRC) are sporadic (only tumor cells have mutation) In sporadic CRCs, it has been proposed that sequential somatic mutations in APC, Ras, and p53 result in progression from normal mucosa to carcinoma Familial adenomatous polyposis (FAP syndrome): rare inherited disease where defective APC causes thousands of polyps (benign tumors) Somatic mutations: changes to DNA that happen after conception to cells 100% risk of developing colon cancer by age 60 other than egg and sperm Accounts for