Neoplasia 4

Neoplasia 4 Fe A. Bartolome, MD, FPASMAP Department of Pathology Our Lady of Fatima University

Chemical Carcinogenesis ,[object Object]

Initiation alone is not sufficient for tumor formation.

Initiation causes permanent DNA damage (mutations). It is rapid and irreversible and has “memory.”,[object Object]

For the change to be heritable, the damaged DNA template must be replicated

For initiation to occur, altered cells must undergo at least one cycle of proliferation so that DNA change becomes fixed,[object Object]

Tumors do not result when the promoting agent is applied before, rather than after, the initiating agent.

The cellular changes resulting from application of promoters do not affect DNA directly and are reversible.,[object Object]

Mutated cells with reduced growth factor requirements

Process of tumor promotion includes multiple steps: proliferation of pre-neoplastic cells, malignant conversion, and tumor progression,[object Object]

Chemical Carcinogenesis: Initiators Direct-Acting Agents ,[object Object]

Most are weak carcinogens; some are chemotherapeutic drugs (e.g. Alkylating drugs)

Risk of induced cancer is low.,[object Object]

Chemical Carcinogenesis: Initiators Indirect-Acting Agents ,[object Object]

present in fossil fuels; animal fats during process of broiling meats; smoked meat and fish

Principal active product: epoxides form adducts with DNA, RNA, and proteins,[object Object]

Example: benzo[a]pyrene light smokers with the susceptible genotype CYP1A1 with 7x higher risk of developing lung cancer,[object Object]

Any gene may be the target  commonly mutated are RAS and p53

Aflatoxin B1  cause G:C  T:A transversion in codon 249 of p53,[object Object]

Degree of risk depends on:Type of UV ray Intensity of exposure Quantity of light-absorbing protective coat of melanin

UVB radiation is the main cause of sunburn and skin cancer although mounting evidence suggests UVA may also play a role. UVB does not penetrate the skin as deeply as UVA but has more energy and therefore does more damage to the skin.

UVB sunlight is directly absorbed by DNA resulting in single strand breaks and the formation of pyrimidinedimers.

Radiation Carcinogenesis Ionizing Radiation ,[object Object]

Lead to formation of reactive oxygen species or free radicals,[object Object]

Intermediate: breast, lungs, salivary glands

Resistant: skin, bone, GIT,[object Object]

Microbial Carcinogenesis Oncogenic RNA Viruses: HTLV type 1 ,[object Object]

Viral integration shows clonal pattern  site of integration identical within all cells of a given cancer,[object Object]

Genes encoding IL-2 & its receptor

Gene for myeloid growth factor granulocyte-macrophage colony-stimulating factor,[object Object]

Microbial Carcinogenesis OncogenicDNAViruses: HPV ,[object Object]

HPV genome integrated into host genome  site of integration random but pattern of integration is clonal,[object Object]

Microbial Carcinogenesis OncogenicDNAViruses: HPV ,[object Object],[object Object]

Microbial Carcinogenesis OncogenicDNAViruses: EBV ,[object Object]

Infects B cells and possibly epithelial cells of the oropharynx via complement receptor CD21,[object Object]

Involves the “hijacking” of several normal signalling pathways,[object Object]

Microbial Carcinogenesis OncogenicDNAViruses: EBV ,[object Object],Encodes a nuclear protein that mimics a constitutively active Notch receptor Transactivates several host genes  cyclin D and src family of proto-oncogenes

Impair immune competence  allow sustained B-cell proliferation

Cause translocations that activate c-MYC oncogene,[object Object]

No consistent pattern of integration in liver cells

Immunologically-mediated chronic inflammation with hepatocyte death  regeneration and genomic damage,[object Object]

Microbial Carcinogenesis Helicobacter pylori ,[object Object]

Implicated in gastric adenocarcinoma and gastric lymphomas

Involves increased epithelial cell proliferation in a background of chronic inflammation  contain genotoxic agents such as ROS,[object Object]

Penetrates into gastric epithelial cells  initiate signalling cascade that mimics unregulated growth factor stimulation

Additional mutations may be acquired (e.g. (11:18) translocation)  cause constitutive activation of NF-κβ,[object Object]

Tumor Immunity Immune surveillance ,[object Object]

(+) lymphocytic infiltrates around tumors and in LN draining sites of cancer

Increased incidence of cancer in immunocompromised individuals

Demonstration of tumor-specific T cells and antibodies,[object Object]

Initially classified as:Tumor-specific antigens ,[object Object],Tumor-associated antigens ,[object Object],[object Object]

Not present in normal cells  do not induce self-tolerance,[object Object],[object Object],[object Object]

Genes silenced during development and activated during malignant transformation,[object Object]

Tumor Immunity Tumor antigens Altered cell surface glycolipids and glycoproteins ,[object Object]

Melanomas: high levels of gangliosides GM2, GD2, and GD3

Target for cancer therapy with specific antibodies,[object Object]

Cancer cells entering the bloodstream form complex thromboemboli with platelets and leukocytes, which are thought to facilitate arrest at ectopic sites, assist interactions with the endothelium, and help in evasion of the immune system. Current data suggest that this phenomenon can be explained by interactions between platelet and/or endothelial P-selectin and carcinoma mucins.

Tumor Immunity Tumor antigens Cell type-specific differentiation antigens ,[object Object]

Typically normal self-antigens  do not induce immune response

Potential targets for immunotherapy and for identifying the tissue of origin of tumors,[object Object]

Tumor Immunity Anti-tumorEffector Mechanisms Cytotoxic T lymphocytes ,[object Object]

Demonstrated in blood and tumor infiltrates of cancer patients,[object Object]

Tumor Immunity Anti-tumorEffector Mechanisms Natural killer cells ,[object Object]

Activated by IL-2 and IL-5; may be activated by tumors that fail to express MHC class I antigens

NKG2D proteins  activating receptors; recognize stress-induced antigens expressed on tumor cells,[object Object]

Tumor Immunity Anti-tumorEffector Mechanisms Macrophages ,[object Object]

Kill tumors by mechanisms similar to those used to kill microbes or by secretion of TNF,[object Object]

Tumor Immunity Anti-tumorEffector Mechanisms Antibodies ,[object Object]

Monoclonal antibody vs. CD20 (B-cell surface antigen)  treatment of lymphomas,[object Object],[object Object],[object Object]

Express arginase arginine essential component of TCR  loss of T cell recognition,[object Object]

Immune response induced by the tumor may inhibit tumor immunity by activation of T-cell inhibitory receptor CTLA4,[object Object],[object Object],[object Object],[object Object]

Clinical Aspects of Neoplasia ,[object Object],Location and impingement on adjacent structures Functional activity (e.g. Hormone synthesis or development of para-neoplastic syndrome) Bleeding and infections due to ulceration of tumor through adjacent surfaces Symptoms due to rupture or infarction Cachexia or wasting

Clinical Aspects of Neoplasia Local and Hormonal Effects ,[object Object]

Hormone production seen in neoplasms arising in endocrine glands  more typical of benign tumor

Neoplasms in the gut  obstruction or intussusception,[object Object]

Melena and hematuria characteristic of neoplasms of the gut and urinary tract,[object Object],[object Object]

Clinical Aspects of Neoplasia Paraneoplastic Syndromes Endocrinopathies ,[object Object]

Cushing syndrome – most common endocrinopathy 50% with small cell CA of lungs; due to excessive corticotropin production,[object Object]

Two processes involved:Osteolysis induced by cancer Production of calcemichumoral substances in extra-osseous neoplasms

Clinical Aspects of Neoplasia Paraneoplastic Syndromes Acanthosisnigricans ,[object Object]

Genetically determined; juveniles or adults,[object Object]

Clinical Aspects of Neoplasia Cancer Cachexia ,[object Object]

Weight loss results equally from loss of fat and lean muscle

Due to increased basal metabolic rate despite reduced food intake,[object Object]

Grading and Staging Cancer Grading ,[object Object]

Provides information about potential behavior of tumor

Of less clinical value than staging,[object Object]

Neoplasia 4

Recommandé

Recommandé

Contenu connexe

Tendances

Tendances (20)

En vedette

En vedette (7)

Similaire à Neoplasia 4

Similaire à Neoplasia 4 (20)

Plus de MD Specialclass

Plus de MD Specialclass (20)

Dernier

Dernier (20)

Neoplasia 4