Ability to Invade and Metastasize • The spread of tumors is a complex process involving a series of sequential steps, may be interrupted at any stage by • either host-related or • tumor-related factors. • 1. subdivided into two phases: invasion of ECM • 2.vascular dissemination, • 3. and homing of tumor cells.
Invasion of Extracellular Matrix (ECM) • ECM is composed of collagens, glycoproteins, and proteoglycans. • tumor cells must interact with the ECM at several stages in the metastatic cascade. A carcinoma first must breach the underlying basement membrane, then traverse the interstitial connective tissue
Invasion of the ECM is an active process that requires four steps • Detachment of tumor cells from each other • Degradation of ECM • Attachment to novel ECM components • Migration of tumor cells
E-cadherins act as intercellular glues • cytoplasmic portions bind to β-catenin • E-cadherin can transmit antigrowth signals by sequestering β-catenin • E-cadherin function is lost in almost all epithelial cancers, • 1. either by mutational inactivation of E-cadherin genes, • 2.by activation of β-catenin genes, • which suppress E-cadherin expression.
The second step in invasion is local degradation of the basement membrane and interstitial connective tissue • Tumor cells may either secrete proteolytic enzymes themselves or induce stromal cells (e.g., fibroblasts and inflammatory cells) to elaborate proteases. • Multiple different families of proteases • matrix metalloproteinases (MMPs), • cathepsin D, • and urokinaseplasminogen activator, have been implicated in tumor cell invasion
metalloproteinase inhibitors are reduced so that the balance is tilted greatly toward tissue degradation • overexpression of MMPs and other proteases have been reported for many tumors
The third step in invasion involves changes in attachment of tumor cells to ECM proteins
Mechanisms of Action of Chemical Carcinogens • Although any gene may be the target of chemical carcinogens, the commonly mutated oncogenes and tumor suppressors, such as RAS and p53, are important targets of chemical carcinogens. Indeed, specific chemical carcinogens,
aflatoxin B1, produce characteristic mutations in the p53 gene, such that detection of the "signature mutation" within the p53 gene establishes aflatoxin as the causative agent. • . Carcinogenicity of some chemicals is augmented by subsequent administration of promoters
e.g., phorbol esters, hormones, phenols, and drugs) that by themselves are nontumorigenic. To be effective, repeated or sustained exposure to the promoter must follow the application of the mutagenic chemical, or initiator. The initiation-promotion sequence of chemical carcinogenesis
activation of an oncogene such as RAS, subsequent application of promoters leads to clonal expansion • Proliferation • Trnasformation n malignant tumor
Chemical carcinogens have highly reactive eletrophile groups that directly damage DNA, leading to mutations and eventually cancer • .Direct-acting agents do not require metabolic conversion to become carcinogenic, while indirect-acting agents are not active until converted to an ultimate carcinogen by endogenous metabolic pathways
cytochrome P-450 may influence carcinogenesis. • Following exposure of a cell to a mutagen or an initiator, • tumorigenesis can be enhanced by exposure to promoters, which stimulate proliferation of the mutated cells. • Examples of human carcinogens include direct-acting (e.g., alkylating agents used for chemotherapy), indirect-acting (e.g., benzopyrene, azo dyes, and aflatoxin), and promoters/agents that cause pathologic hyperplasias of liver, endometrium.
Radiation Carcinogenesis • whatever its source (UV rays of sunlight, x-rays, nuclear fission, radionuclides) is an established carcinogen • Unprotected miners of radioactive elements have a 10-fold increased incidence of lung cancers.
Natural UV radiation derived from the sun can cause skin cancers (melanomas, squamous cell carcinomas, and basal cell carcinomas). • greatest risk are fair-skinned people who live in locales such as Australia and New Zealand that receive a great deal of sunlight.
Ionizing radiation causes chromosome breakage, translocations, and, less frequently, point mutations, leading to genetic damage and carcinogenesis • .UV rays induce the formation of pyrimidinedimers within DNA, leading to mutations. Therefore UV rays can give rise to squamous cell carcinomas and melanomas of the skin.