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Neoplasia 2

Molecular basis of multistep carcinogenesis
No single genetic alteration is sufficient to induce cancers in vivo. Multiple controls exerted by all three categories of genes-oncogenes, tumor suppressor gene and apoptosis- regulating genes must be lost for emergence of cancer cells. This best exemplified in adenoma- carcinoma of colon. The evolution of adenoma to carcinoma is marked by increasing and additive effect of mutations, affecting ras, APC, P53 and other unidentified gene on 18q.


The accumulation of mutation, resulting perhaps from genetic instability of cancer cells, may be promoted by loss of p53, DNA repair gene or both. Gene that regulate cellular proliferation in a more or less tissue- specific manner, such as APC, NF-1 and Rb are called gate keeper genes, where those regulate genomic stability (DNA repair genes) are called caretaker genes. These latter genes regulate the like hood of mutation in the gatekeeper genes.

Biology of tumor growth

Kinetic of tumor cell growth. Three variables influence tumor cell growth. Doubling time of tumor cells: cell cycle of transformed cells has the same five phases noted in normal cell, the total cell cycle for many tumors is equal to or longer than corresponding normal cells, hence progressive and rapid tumor growth cant always be ascribed to a shortening of tumor cell cycle time. Growth fraction: refer to proportion of cells within the tumor population that are in replicative pool.


3. Cell production and loss: tumor cell accumulation resulting in progressive growth of tumors cab be best explained by an imbalance between cell production and loss, in some tumor ( those with high GF) the imbalance is large, resulting in more rapid growth. The rate of tumor growth depend on the GF and the degree of imbalance tumor cell production and loss, high GF as in certain lymphoma is associated with rapid growth. Susceptibility of tumors to chemotherapy, because most anti-neoplastic agents act on dividing cells, tumors with higher GFs are the most susceptible to anticancer agents. They are also the most rapidly growing if left untreated.. Latent period of tumors: if all descendants of an originally transformed cells remained in the replicative pool, most tumors would become clinically detectable within few months after the initiation of tumor cell growth

Tumor angiogenesis. Because tumor cells similar to normal cells, need O2 to survive, vascularization of tumor by host derived blood vessels has profound influence of tumor growth. In rapidly growing tumors, the rate of growth some times exceed the pace of vascularization causing area of ischemic necrosis. Vascularization of tumor is effected by tumor associated angiogenic factors released from tumor cells or inflammatory cells (macrophages) that enter the tumor. Two most important tumor angiogenic factors are vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF).



Tumor progression and heterogeneity. Tumor progression refer to phenomenon whereby tumors become progressively more aggressive and acquire greater malignant potential. Progression is related to the sequential appearance within the tumor of cells that differ with respect to invasiveness, rate of growth, ability to form metastasis and ability to evade immunosurvellance. Thus a clinically detectable tumor , although monoclonal, is usually made of phenotypically and heterogeneous cells. The heterogeneity is believed to result from genetic instability of tumor cells, which are subject to a high rate of random mutations, possibly because of loss of P53, DNA repair gene, or both.


Mechanism of invasion and metastasis Invasion of extracellular matrix: Tumor cells must attach to, degrade and penetrate extracellular matrix at several steps of metastasis cascade. Invasion can be resolved into 4 steps: detachment tumor cells from each other: adhesion molecules as cadherin been down regulated leading to decrease cells cohesiveness of tumor. Attachment to matrix component: tumor cells bind to laminin and fibronectin via cell surface receptors. Degradation of extracellular matrix: tumor cells secret proteolytic enzyme that degrade the matrix component and create passageway for migration. Migration of tumor cells: implicated in this process are autocrine motility factors and cleavage products of extracellular matrix.


b. Vascular dissemination and homing of tumor cells. In circulation tumor cells form emboli by aggregation and by adhering to circulating leukocytes, particularly platelets. Aggregates tumor cells are afforded some protection from antitumor host effector cells. The site where tumor emboli lodge and produce secondary growth is influence by several factors. Vascular and lymphatic drainage from site of primary tumor. Interaction of tumor cells with organ specific receptors. The microenvironment of organ or site (e.g: tissue rich in protease inhibitors might be resistance to penetration by tumor cells)

Carcinogenic agents.

Radiation and many chemicals are known to be carcinogenic in human and animals. Chemical carcinogenesis: divided into tow stages. 1.Initiation : refer to induction of certain irreversible changes (mutations) in genome of cells. Initiated cells are not transformed cells, they do not have growth autonomy or unique phenotypic characteristics, in contrast to normal cells, however, they give rise to tumor when appropriately stimulated by promoting agents.


2. promotion: refer to process of tumor induction in previously initiated cells by chemicals refer as promoters, the effect of promoters in relatively short lived and reversible, they do not affect DNA and are non tumorigenic by themselves. Mechanism s of initiation: Vast majority of chemicals referred as procarcinogens because they require metabolic activation in vivo to produce ultimate carcinogen Only a few alkaylating and acylating agents are direct-acting carcinogens. The activation of procarcinogens in most cases depends on microscopical cytochrome p-450 oxygenases. Individual who inherit highly inducible forms of these enzymes incur a higher risk of smoking related lung cancers.

Carcinogenic chemicals : Alkylating agent: , include direct acting agents such as cyclophosphamide used for cancer treatment as well as immunosuppressant can cause other form of cancers. Aromatic hydrocarbons: present in cigarette smoke and has role in pathogenesis of lung cancer. Azo dye: aniline die used in rubber industry responsible for bladder cancer. Naturally occurring carcinogens : Aflatoxin B, product of fungus Aspergillus flavus are potent hepatocarcinogen. Nitrosamines: can be synthesized in stomach from ingested nitrite has role in gastric cancer.


Viral and microbial carcinogenesis:Variety of RNA and DNA viruses are known to cause cancer.Oncogenic viruses typically integrate their genomes into host cells and enter a period of “latency”HPV, EBV, HBV.HPV (type 1, 2, 4 and 7) cause benign squamous papilloma(wart).HPV (16,18) found in uterine cervix cancer in 90%.EBV member of herpes virus family and associated with four tumors including Burkitt's lymphoma, nasopharyngeal cancer, B-cell lymphoma in immunocompromised patients and Hodgkin disease.Hepatitis B virus close association with hepatic cancer

Host defense against tumor

Tumor antigen: Tumor antigen can be classified into two groups, tumor specific antigen which present only in tumor cells and tumor associated antigen which present on tumor cells and normal cells. Immunosurvellance: A putative Immunosurvellance against tumor has been hypothesized and evidence of its coexistence consist of Increase incidence of cancer in congenital or acquired immune deficiency. Increase susceptibility to EBV and EBV associated lymphoma in boys with X-linked immunodeficiency.



Tumor may escape Immunosurvellance by: Selective out growth of antigen-negative variant. Loss or decrease expression of histocompatibility antigen, thus becoming less susceptible to cytotoxic T-cell lysis. Tumor induced immunosuppression. Failure of sensitization because tumor cells do not express costimulatory molecules. Apoptosis of cytotoxic of T cells because tumor cells express Fas so T- cells undergo death when engaged by tumor associated Fas.


Clinical features of tumors :Local and hormonal effects as follow:Related to location : intracranial tumor (pituitary) can expand and destroy remaining tissue, giving rise to an endocrine disorder, tumor of GIT can cause obstruction.Hormone production: tumor of endocrine organs can elaborate hormones, this is more common in benign than malignant tumors. Cancer cachexia: Loss of body fat , wasting and profound weakness, the basis of cachexia is multifactorial.Loss of appetite.Metabolic changes lead to reduce synthesis and storage of fat.Production of tumor necrosis factor-α by activated macrophages and other hormonal factors.

Grading and staging of tumor

The grade and stage of malignant tumors provide a semiquantative estimate of the clinical gravity of tumor Grading is based on the degree of differentiation and the number of mitosis within the tumor. Cancers are classified as grade I to IV with increasing anaplasia. in general high grade tumor are more aggressive than lower grade tumor


Grading is imperfect because: Different parts of same tumor may display different degree of differentiation. The grade of tumor may change as tumor grows. Staging is based on the anatomic extent of the tumor. Relevant to staging are the size of primary tumor and the extent of local and distant metastasis. Two methods for staging TNM (tumor, node, metastasis). AJC(American joint committee) system. Both histologic grading and clinical staging are valuable for prognosis and for therapy planning.

<=2cm

2-5cm
>5cm

Laboratory diagnosis of cancer

1. Histologic methods. Histologic examination is the most important method for diagnosis, proper diagnosis is greatly aided by. Available of all relevant clinical data. Adequate preservation and sampling of specimen. In some cases, examination of frozen specimen to detect cell surface receptors.


2. Fine needle aspiration: Involve aspiration of cells and fluids from tumors or masses that occur in readily palpable site (e.g: breast, thyroid and lymph nodes). The aspirated cells are smeared and stained then examined. 3. immunohistochemistry: Involve detection of cells products or surface markers by monoclonal antibodies. The binding of antibodies can be revealed by fluorescent labels or chemical reactions that result in the generation of a colored products.


This technique is useful in the following settings: Diagnosis of undifferentiated tumor by detection of tissue specific intermediate filaments. Categorization of leukemia and lymphoma by using monoclonal antibodies specific for various lympho-hematopoietic cells. Determination of site of origin of metastasis by using reagents that identify specific cell type (e.g: prostatic specific antigen in prostatic cancer). Detection of molecules that have prognostic or therapeutic significance as cerb-2 in breast cancer.

4. DNA probe analysis. Involve polymerase chain reaction (PCR) or (FISH) analysis. Mostly used in diagnosis of lymphoid neoplasm because such tumors are associated with clonal rearrangement of T- cell and B-cell antigen receptor gene. Detection of oncogene such as N-myc is also valuable in prognosis of certain tumors. Hereditary predisposition of certain tumors ( breast cancer and some neuroendocrine tumors) can be detected by mutational analysis of BRCA-1 and BRCA-2 with RET gene.


5. Flow Cytometry.Measurement of DNA content of tumor cells is useful because with several tumors there is a relationship between abnormal DNA content and prognosis.6. Tumor markers.Tumor derived or tumor associated molecules that can be detected in blood or other body fluids.They are not primary method for diagnosis but rather adjuncts to diagnosis.Also valuable in determining the response to therapy.Examples : CEA colon of pancreas, colon, stomach and breast.Α-fetoprotein in liver and testicular tumors.

Cancer Treatment

Chemotherapy Cytotoxic drugs + body defenses Single agent Combination chemotherapy Avoids single agent resistance Can use lower dose Better remission and cure rate

Cancer Treatment

Radiation targets DNA kill tumor without damage to surrounding tissues tumor must be accessible

Cancer Treatment

Surgery method of choice can remove entire tumor debulking adjuvant chemotherapy or radiation palliation

Cancer Treatment

ImmunotherapyNonspecific enhancement of the immune system – interferons or interleukinsprotect against recurrenceeliminates cancer cells onlyT- cell based or antibody responsesConjugated antibodies


Cancer Treatment
Targeted Therapies Drugs that target the processes of cancer cells specifically Thalidomide Vaccines