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Neoplasia (Hallmarks of Cancer (Self-Sufficiency in Growth Signals (normal…

- - - - some emboli by aggregating + adhering to circulating leukocytes, partic platelets--> some protection from antitumor host effector cells.
      - Most tumor cells circulate as single cells.
    - - are there genes whose principal or sole contribution to tumorigenesis is to control metastases? candidates: SNAIL and TWIST (TFs whose primary function: promote EMT: cells :arrow_down: epithelial (Ecadherin) + :arrow_up: mesenchymal markers (vimentin, smooth muscle actin) + phenotypic alterations (polygonal epithelioid cell shape--> spindly mesenchymal, :arrow_up: production of proteolytic Es that promote migration + invasion)
        Loss of Ecadherin: key event in EMT, and SNAIL and TWIST are transcriptional repressors :arrow_down: Ecadherin expression.
      - Perhaps both, w/ aggressive tumors acquiring a metastasis permissive gene expression pattern early in tumorigenesis that requires some additional random mutations to complete the metastatic phenotype
        
        theory of tumor progression: as tumors grow, cells randomly accumulate mutations, creating subclones; only a small subpopulation contains all mutations necessary for metastasis.
        
        Recent experiments: a subset of breast cancers has a gene expression signature similar to that found in metastases, although no clinical evidence for metastasis apparent; most if not all cells acquire a predilection for metastatic spread early on, during primary carcinogenesis. Metastasis is an intrinsic property of tumor developed during carcinogenesis.
    - - Locomotion
        
        tumor cell–derived cytokines, such as autocrine motility factors
        
        cleavage products of matrix components (coll, laminin) + some
        GFs (ILGF I and II): chemotactic activity for tumor cells.
        
        Stromal cells also produce paracrine effectors of cell motility, such as hepatocyte GF/scatter factor (HGF/SCF)-->binds to Rs on tumor cells. [HGF/SCF] elevated at advancing edges of highly invasive brain tumor glioblastoma multiforme, supporting their role in motility.
      - changes in attachment of tumor cells to ECM proteins.
        
        Normal epithelial cells have Rs (integrins) for basement membr laminin + colls that are polarized at their basal surface; hat are polarized at their basal surface--> help to maintain cells in a resting, differentiated state; Loss of adhesion in normal cells--> apoptosis
        
        matrix modified in ways that promote invasion + metastasis; ex cleavage of basement membr prs, coll IV + laminin--> novel sites that bind to Rs on tumor cells + stimulate migration
      - degradation of basement membr + interstitial con tissue: Tumor cells themselves or induce stromal cells to elaborate proteases
        
        MMP9 (a gelatinase)--> cleaves type IV coll of epithelial + vascular basement membrane + stimulates release of VEGF from ECM sequestered pools + levels of MMP inhibitors reduced
        
        Multiple different families of proteases: MMPs, cathepsin D, and urokinase plasminogen activator
      - LOOSENING OF INTERCELLULAR JUNCTIONS:
        
        epithelial to mesenchymal transition: downregulate certain epithelial markers (e.g., Ecadherin) + upregulate certain mesenchymal markers (e.g., vimentin, smooth muscle actin)--> phenotypic alterations: polygonal epithelioid-->spindly mesenchymal shape
        
        E-cadherin function lost in almost all epithelial cancers by: by ,
        
        mutational inactivation of E-cadherin genes,
        
        activation of β-catenin genes-->به APC
        متصل میشود و E-cadherin را رها
        
        inappropriate expression of SNAIL + TWIST, which suppress E-cadherin expression
    - - site of extravasation + organ distribution of metastases
        
        many cases natural pathways of drainage do not explain distribution of metastases; ex: lung cancers: involve adrenals quite often but almost never spread to skeletal muscle. Such organ tropism may be related to:
        
        Expression of adhesion molecules by tumor cells whose ligands are expressed preferentially on endothelium of target organs
        
        tumor cells must be able to colonize site (favorable soil) ex: although well vascularized, skeletal muscles are rarely site of metastases
        
        Expression of chemokines + their Rs: Human breast cancer cells express high levels of CXCR4 + CCR7: ligands highly expressed only in organs to which breast cancer cells metastasize
        
        generally can be predicted by location of primary tumor + its vascular/lymphatic drainage. Many metastasize to organ that presents first capillary bed they encounter after entering circulation
      - tumor cells quite inefficient in colonizing distant organs; millions shed daily + detected in blood+ small foci in bone marrow, even in patients in whom gross metastatic lesions never develop; dormancy: prolonged survival of micrometastases w/o progression, well described in melanoma + breast + prostate cancer.
      - molecular mech: tumor cells secrete cytokines, GFs, proteases that act on resident stromal cells, which in turn make metastatic site habitable for cancer cell
  - - - Warburg effect/ aerobic glycolysis--> 2 ATP/Glc v. 36 but generates more C: in rapidly growing cells glc is primary source of carbons are used for synth of lipids + other metabolites needed for nucleic acid synth---> tumors adopting aerobic glycolysis, ex Burkitt lymphoma, are most rapidly growing of human cancers
      - “glucose hunger” of such tumors used to visualize tumors by PET scanning (Most tumors are PET +), (injected w/ 18 Ffluorodeoxyglucose, a nonmetabolizable derivative of Glc)
  - - - Many proteases can release angiogenic basic FGF stored in ECM; conversely, three potent angiogenesis inhibitors—angiostatin, endostatin, and vasculostatin—produced by proteolytic cleavage of plasminogen, coll, and transthyretin, respectively; TSP1 produced by stromal fibroblasts
      - hypoxiainducible factor1α (HIF1α) is continuously produced; normoxic settings: von Hippel–Lindau pr (VHL) binds to HIF1α, leading to ubiquitination + destruction of HIF1α.
      - hypoxic conditions--> prevents HIF1α recognition by VHL + not destroyed--> HIF1α translocates to nucleus--> *transcription of its target genes, (VEGF)
        VHL acts as a tumor suppressor gene-->germline mutations--> hereditary renal cell cancers, pheochromocytomas, hemangiomas of CNS, retinal angiomas, and renal cysts (VHL syndrome
      - angiogenesis inducer (VEGF) + inhibitor (thrombospondin1 TSP1); Early on, most tumors don't induce angiogenesis + remain small / in situ for yrs until angiogenic switch terminates this stage of vascular quiescence. Normal p53 induces synth of TSP1.
      - tumor cells-->VEGF + FGF-β--> incr expression of ligands that activate Notch signaling pathway--> branching + density of new vessels
    - - Perfusion supplies needed nutrients and oxygen,
      - newly formed endothelial cells stimulate growth of adj tumor cells by secreting GFs, such as ILGF, PDGF, GMCS-F
  - - - Xeroderma Pigmentosum: incr risk for cancers of sunexposed skin. Several pr involved in nucleotide excision repair, and an inherited loss of any one of these-->xeroderma pigmentosum
      - Diseases w/ Defects in DNA Repair by Homologous Recombination
        
        a group of auto recessive disorders, phenotype complex: predisposition to cancer..., charac by hypersensitivity to DNA damaging agents
        
        ionizing radiation in
        
        Bloom syndrome: developmental defects
        
        ataxia telangiectasia: neural symptoms; gene mutated: ATM, (encodes a pr kinase imp in recognizing DNA damage + initiating p53 activation)
        
        DNA crosslinking agents (nitrogen mustard) in Fanconi anemia;
        
        BRCA 1+ 2: 50% of familial breast cancer; cells lacking these genes--> chromosomal breaks + severe aneuploidy. BRCA1 forms a complex with other proteins in the homologous recombination pathway and also is linked to the ATM kinase pathway; Similar to other tumor suppressor genes, both copies of must be inactivated; these genes rarely inactivated in sporadic cases of breast cancer. In this regard diff from others inactivated in both familial + sporadic cancers.
        
        BCRA1--> :arrow_up: risk of epithelial ovarian cancers + slightly :arrow_up: risk of prostate cancer.
        
        BRCA2: :arrow_up: risk of breast cancer in men + women, as well as cancer of ovary, prostate, pancreas, bile ducts, stomach, melanocytes, and B cells
      - Hereditary Nonpolyposis Colon Cancer Syndrome: familial carcinomas of colon affecting predominantly cecum + proximal colon
        
        Mutations in at least 4 mismatch repair genes have been found to underlie HNPCC
        
        characteristic finding: microsatellite (tandem repeats of 1-6 ns found throughout genome) instability (MSI): In normal ppl length remains constant; in HNPCC incr/decr; Although HNPCC accounts for only 2-4% of all colonic cancers, MSI can be detected in about 15% of sporadic cancers.
      - Cancers Resulting From Mutations Induced by Regulated Genomic Instability: Lymphoid Neoplasms
    - - Persistent chronic inflammation in response to microbial infections or as part of an AI reaction: Barrett esophagus, ulcerative colitis, H. pylori gastritis, hepatitis B and C, and chronic pancreatitis.
        injury/regeneration sequence-->genomic instability
        
        Persistent cell replication + reduced apoptosis: risk of acquiring mutations
        
        inflammatory cells-->ROS--> additional DNA damage in rapidly dividing cells.
      - virtually every tumor infiltrated by immune system (adaptive + innate): protective but: exert tumor promoting activity by producing GFs + inflicting additional DNA damage (ROS)
  - - - In 85-95% of cancers: due to upregulation of telomerase
      - A few tumors use other mechanisms, termed alternative lengthening of telomeres, which probably depend on DNA recombination
    - - • Short telomeres recognized by DNA repair machinery as dsDNA breaks--> cell cycle arrest + senescence; cells in which TP53/RB mutations, nonhomologous endjoining pathway activated, joining shortened ends of two chromosomes.
      - • results in dicentric chromosomes pulled apart at anaphase--> new dsDNA breaks; resulting genomic instability from repeated bridge–fusion–breakage cycles --> mitotic catastrophe (massive apoptosis)
  - - - intrinsic pathway (TP53 an important proapoptotic gene induces apoptosis in cells unable to repair DNA damage + unrestrained action of growth promoting genes); integrity of mitC outer membr regulated by BCL2 family of prs
        
        antiapoptotic BCL2 and BCLXL
        
        BH3-only prs (BAD, BID, and PUMA) reg balance btw pro + antiapoptotic; promote apoptosis by neutralizing actions of antiapoptotic prs
        
        proapoptotic BAX and BAK; BAD, BID--> caspase9--> executioner caspases
      - extrinsic (death receptor) pathway: Fas (CD95)
      - best-established: role of BCL2: 85% of B cell lymphomas of follicular type carry a characteristic t(14;18)--> overexpression of BCL2--> incr BCL2/ BCLXL buffer-->protecting lymphocytes from apoptosis; bc it arises through reduced cell death rather than explosive cell proliferation, tend to be (slowgrowing) compared to other lymphomas
  - - - 1.inactivation of APC tumor suppressor gene -->colon epithelial hyperplasia
      - loss of DNA methylation--> early adenomas
      - activation of RAS--> intermediate adenoma
      - loss of a tumor suppressor gene on 18q--> late adenoma
      - loss of TP53-->carcinoma
  - - - mutation: continuous mitogenic signals to cells, even in absence of GF
      - overexpression (more common): EGF R family
        
        ERBB1 in 80% of SCC of lung, 50% or more of glioblastomas, and 80% to 100% of epithelial tumors of head + neck
        
        HER2/NEU (ERBB2) in 25-30% of breast cancers (high level-->poor prognosis; antiHER2/ NEU Abs beneficial) + adenocarcinomas of lung, ovary, salivary glands
    - - RAS
        
        most commonly mutated protooncogene: 30% of all tumors + frequency even higher in some specific cancers (e.g., colon and pancreatic adenocarcinomas
        
        Activated RAS (GTP)--> proliferative signals to nucleus along two pathways: RAF/ERK/MAP kinase + PI3 kinase/AKT pathway
      - ABL: non receptor associated
        
        chronic myelogenous leukemia + certain acute leukemias: t (9;22): ABL-BCR--> unleashes a constitutive tyrosine kinase activity--> BCRABL protein activates all of signals downstream of RAS
        
        dramatic clinical response to BCRABL kinase inhibitors: imatinib mesylate; also an ex of concept of oncogene addiction: a tumor profoundly dependent on a single signaling molecule; BCRABL signaling can be seen as central lodgepole around which structure is built--> If lodgepole removed-->structure collapses; acquired resistance of tumors to BCRABL inhibitors: outgrowth of a subclone w/ a mutation in BCRABL that prevents binding of drug
    - - acquiring ability to synthesize same growth factors to which they are responsive:
        
        many glioblastomas secrete plateletderived growth factor (PDGF) and express the PDGF receptor
        
        many sarcomas make both transforming growth factorα (TGFα) and its receptor
      - interaction w/ stroma--> tumor cells send signals to *normal c in stroma--> produce GFs that promote tumor growth.
    - - MYC: NMYC + LMYC genes amplified in neuroblastomas + SSC of lung;
        
        *(ex: CDKs)/repress(ex: CDKIs) transcription of other genes
        
        key regulator of Warburg effect,+ incre utilization of Glu
    - - Transient of R--> signal transducing pr on inner memb
      - 2nd messengers/cascade of signal transduction molecules-->nucleus
      - GF-b-receptor
      - regulatory factors*-->initiate + regulate DNA transcription
      - Entry + progression of cell into theG cell cycle-->cell division
    - - The Normal Cell Cycle fig 5-20
      - Alterations in Cell Cycle Control Proteins in Cancer Cells: senescence + apoptosis must be disabled to allow unopposed action of oncogenes.
        
        incr expression
        
        cyclin D: in many cancers, including..a subset of lymphomas and plasma cell tumors
        
        CDK4: in melanomas, sarcomas, and glioblastomas
        
        CDKIs frequently
  - - - mechanisms that enforce the G1/S
        transition.
        
        cyclin D–CDK4/6 complexes phosphorylate Rb, inactivating the protein and releasing E2F
        
        Rb is in its hypophosphorylated
        active form, and it binds to and inhibits the E2F family
      - Rb binds to a variety of other TFs that regulate cell differentiation--> couples control of cell cycle progression at G0
        G1 w/ diff (explain how differentiation is associated w/ exit from cell cycle)
      - loss of normal cell cycle control central to malignant transformation + at least one of 4 key regulators of cell cycle (CDKN2A, cyclin D, CDK4, Rb) is mutated in most human cancers.
    - - in healthy cells: short halflife (20 mins) bc of MDM2 (destroys p53); cell stressed--> *sensors (pr kinases like ATM (ataxia telangiectasia mutated)--> catalyze posttranslational modifications in p53 that release it from MDM2
      - functions mediated by antigrowth + repressing progrowth genes; (How could p53, a transcriptional activator, repress gene function? p53 can transcriptionally certain miRNAs (miRNAs prevent translation of their target genes))
      - Biallelic loss of TP53 found in every cancer type
        
        most cases: inactivating mutations in both alleles acquired in somatic cells.
        
        some inherit a mutant allele--> Li-Fraumeni syndrome (like Rb two hit..): 25x greater chance of developing malignant tumor by age 50; spectrum of tumors varied, most common types: sarcomas, breast cancer, leukemia, brain tumors, carcinomas of adrenal cortex. Compared w/ sporadic tumors, develop tumors at a younger age + may develop multiple primary tumors.
    - - Mutations: in 100% of pancreatic + 83% of colon cancers, min 1 pathway component mutated. In many cancers, however, occurs downstream + these cells can then use other elements of TGFβ (immune system suppression + evasion or promotion of angiogenesis; in many latestage tumors *EMT to facilitate tumor progression)
        
        type II R: in cancers of colon, stomach, and endometrium.
        
        SMAD4 (involved in TGFβ signaling): common in pancreatic cancers.
    - - contact inhibition: tumor suppressor gene NF2 (merlin)--> facilitates E-cadherin mediated contact inhibition; Homozygous loss of NF2--> neurofibromatosis.
      - APC + catenin + WNT; APC mutations are seen in 70% to 80% of sporadic colon cancers; ppl born w/one mutant allele typically found to have hundreds -thousands of adenomatous polyps in colon by their teens or 20s; these polyps show loss of other APC allele. Almost invariably, one or more polyps undergo malignant transformation, colonic cancers that have normal APC genes show activating mutations of βcatenin that render them refractory to degrading action of APC.
        adenomatous polyposis coli (APC): development of numerous adenomatous polyps in colon that have a very high incidence of transformation into colonic cancers; consistently show loss of APC
- - - - Childhood retinoblastoma: carriers of mutant gene have a 10,000x risk of developing retinoblastoma.
      - Tumors within this group often associated w/ a specific marker phenotype: may be multiple benign tumors in affected tissue, as occurs in familial polyposis of the colon + in multiple endocrine neoplasia; Sometimes abnormalities in tissue that are not target of transformation (Lisch nodules and caféaulait spots in neurofibromatosis type 1)
    - - all common types of cancers that occur sporadically have been reported to occur in familial forms where pattern of inheritance is unclear. Ex: carcinomas of colon, breast, ovary, and brain.
      - Features charac: early age at onset, tumors arising in 2 or more close relatives of index case, and sometimes multiple or bilateral tumors.
      - not associated w/ specific marker phenotypes. ex: in contrast w/ familial adenomatous polyposis syndrome, familial colonic cancers do not arise in preexisting benign polyps.
      - In general, siblings have a relative risk btw 2 and 3. predisposition to tumors is dominant, but incomplete penetrance / multifactorial inheritance cannot be easily ruled out
  - - - • Squamous metaplasia + dysplasia of bronchial mucosa, in habitual smokers--> lung cancer
      - • Endometrial hyperplasia + dysplasia, in women w/ unopposed estrogenic stimulation--> endometrial carcinoma
      - • Leukoplakia of oral cavity, vulva, or penis--> squamous cell carcinoma
      - • Villous adenomas of colon--> colorectal carcinoma
- - - - encapsulated: as adenomas slowly expand, most develop an enclosing fibrous capsule (probably derived from stroma of host tissue as parenchymal cells atrophy under pressure of expanding tumor. The stroma of the tumor itself also may contribute)
      - not encapsulated, discretely demarcated: ex leiomyoma of uterus from surrounding smooth muscle by a zone of compressed and attenuated normal myometrium; nonetheless, a well-defined cleavage plane exists
      - neither encapsulated nor discretely defined; partic likely to be seen in some benign vascular neoplasms of dermis.
  - - - (1) seeding within body cavities: when neoplasms invade a natural body cavity; partic charac of cancers of ovary (often cover peritoneal surfaces widely) implants literally may glaze all peritoneal surfaces and yet not invade underlying tissues. Neoplasms of CNS (medulloblastoma / ependymoma) may penetrate cerebral ventricles + be carried by CSF to reimplant on meningeal surfaces, either within brain or in spinal cord.
      - (2) lymphatic spread: more typical of carcinomas; pattern of lymph node involvement depends principally on site of primary neoplasm + natural pathways of local lymphatic drainage.
        
        Lung carcinomas arising in respiratory passages metastasize first to regional bronchial lymph nodes--> tracheobronchial + hilar nodes.
        Carcinoma of breast u. arises in upper outer quadrant = first spreads to the nodes. (medial breast lesions may drain through chest wall to nodes along internal mammary artery); in both instances, supraclavicular + infraclavicular nodes may be seeded.
        
        some cases: cancer cells traverse lymphatic channels within immediately proximate nodes to be trapped in subsequent lymph nodes--> skip metastases; cells may traverse all of lymph nodes ultimately to reach vascular compartment by way of thoracic duct.“sentinel lymph node”: first regional lymph node that receives lymph flow from a primary tumor (identified by injection of blue dyes / radio labeled tracers near primary tumor); although enlargement of nodes near a primary neoplasm should arouse concern for metastatic spread, it does not always imply cancerous involvement: necrotic products of neoplasm + tumor Ags often evoke immunologic responses in nodes, such as hyperplasia of follicles (lymphadenitis) and proliferation of macrophages in the subcapsular sinuses (sinus histiocytosis). Thus, histopathologic verification of tumor within an enlarged lymph node is required.
      - (3) hematogenous spread: favored by sarcomas but carcinomas use it as well; arteries penetrated less than veins.
        venous invasion: bloodborne cells follow venous flow + tumor cells often stop in first capillary bed encountered; Since all portal area drainage flows to liver, and all caval blood flows to lungs--> liver + lungs are most frequently involved secondary sites in hematogenous dissemination.
        
        Cancers arising near vertebral column often embolize through paravertebral plexus; this pathway probably is involved in frequent vertebral metastases of carcinomas of thyroid + prostate.
        
        Certain have a propensity to grow within veins.
        Renal cell carcinoma often invades renal vein to grow in a snakelike fashion up IVC
        Hepatocellular carcinomas often penetrate portal + hepatic radicles to grow within them into main venous channels. Remarkably, such IV growth may not be accompanied by widespread dissemination
        
        anatomic localization of a neoplasm + venous drainage cannot wholly explain systemic distributions of metastases. ex prostatic carcinoma preferentially spreads to bone, bronchogenic carcinomas tend to involve adrenals + brain, and neuroblastomas spread to liver + bones. Conversely, skeletal muscles, although rich in capillaries, rarely site of secondary deposits.
  - - - pleomorphism (variation in size and shape)
      - nuclei are extremely hyperchromatic + large, nuclear tocytoplasmic ratio that may approach 1 : 1 instead of the norm 1 : 4 or 1 : 6
      - Giant cells: possess either one enormous nucleus or several nuclei
      - nuclei are variable and bizarre in size and shape,
      - chromatin is coarse and clumped, and nucleoli may be of astounding size
      - mitoses often are numerous and distinctly atypical; anarchic multiple spindles-->tripolar or quadripolar mitotic figures
      - fail to develop recognizable patterns of orientation to one another (lose normal polarity) may grow in sheets, with total loss of communal structures, such as glands or stratified squamous architecture
    - - cells: considerable pleomorphism, often hyperchromatic abnormally large nuclei, Mitotic figures more abundant + frequently appear in abnormal locations within the epithelium; considerable architectural anarchy
      - carcinoma in situ: dysplastic changes are marked and involve the entire thickness of the epithelium; a preinvasive stage of cancer
- - - - well differentiated: 1
      - moderately differentiated: 2
      - poorly differentiated: 3
      - undifferentiated: 4
    - - TMN
        وهرچه TMN بالاتر -->prognose بدتر
        
        اندازه تومور است و در تومورهای مختلف فرق میکند م در مورد سرطان پستان :
        T1 : 2cm زیر T2 : 2-3cm T3 : 3-5cm
        T4
        
        N0, N1, N2, and N3 progressively advancing node involvement;
        
        M0 and M1 reflect absence and presence, respectively, of distant metastases
      - AJC system: مخصوص آمریکاست و از
        صفر تا چهار مرحلهبندی میشود incorporating the size of primary lesions and the presence of nodal spread and of distant metastases
  - - - some correlation btw size + extent of spread of cancer and severity of cachexia. However, cachexia is not caused by nutritional demands of the tumor; in patients calorie expenditure remains high + BMR :arrow_up:, despite :arrow_down: food intake. This is in contrast w/ :arrow_down: metabolic rate that occurs as an adaptive response in starvation.
      - TNF produced by MQs or by tumor cells themselves--> suppresses appetite + inhibits lipopr lipase, inhibiting release of free FAs from lipoprs.
      - a pr mobilizing factor called proteolysis inducing factor (causes breakdown of skeletal muscle prs by ubiquitin proteosome pathway) detected in serum of cancer patients. Other molecules with lipolytic action also have been found.
      - no satisfactory treatment for cancer cachexia other than removal of underlying cause, the tumor.
    - - appear in 10-15% of patients + their clinical recognition is important for several reasons:
        
        • may mimic metastatic disease, thereby confounding treatment.
        
        • pathologic changes may be associated w/ significant clinical illness and may even be lethal.
        
        • may represent earliest manifestation of an occult neoplasm.
      - most common syndromes:
        (neoplasms most often associated with these and other syndromes are lung and breast cancers and hematologic malignancies)
        
        Hypercalcemia: multifactorial
        
        most important mechanism: synth of a PTH-related pr (PTHrP) by tumor cells.
        
        other tumor derived factors, such as TGFα, a polypeptide factor that activates osteoclasts, and active form of vit D.
        
        widespread osteolytic metastatic disease of bone; (of note, however, hypercalcemia resulting from skeletal metastases is not a paraneoplastic syndrome)
        
        Cushing syndrome
        u. ectopic production of ACTH or ACTH like polypeptides by cancer cells, as occurs in SCC of lung.
        
        nonbacterial thrombotic endocarditis
      - Sometimes one tumor induces several syndromes concurrently. ex: bronchogenic carcinomas may elaborate products identical to or having the effects of ACTH, ADH, PTH, serotonin, hCG, and other bioactive substances.
      - Paraneoplastic syndromes also may manifest as hypercoagulability, leading to venous thrombosis and nonbacterial thrombotic endocarditis; Other manifestations: clubbing of fingers + hypertrophic osteoarthropathy in patients w/ lung carcinomas
  - - - Fine needle aspiration: aspiration of cells from a mass, followed by cytologic examination of smear. used most commonly w/ readily palpable lesions affecting breast, thyroid, lymph nodes, and salivary glands. Modern imaging techniques permit extension of the method to deeper structures, such as liver, pancreas, and pelvic lymph nodes.
      - excision
        
        frozen section: in determining nature of a mass lesion or in evaluating regional lymph nodes in a patient w/ cancer for metastasis; sample is quickfrozen + sectioned + evaluation within minutes
        
        When excision of a lesion not possible, selection of an appropriate site for biopsy of a large mass requires awareness that margins may not be representative + center may be largely necrotic.
      - immunocytochemistry
        
        Detection of cytokeratin by specific monoclonal Abs labeled w/ peroxidase points to a diagnosis of undifferentiated carcinoma rather than large cell lymphoma.
        
        detection of PSA in metastatic deposits by immunohistochemical staining allows definitive diagnosis of a primary tumor in prostate.
        
        detection of estrogen Rs allows prognostication + directs therapeutic intervention in breast cancers.
      - Flow cytometry: used routinely in classification of leukemias and lymphomas; fluorescent Abs against cell surface molecules + diff Ags used to obtain phenotype of malignant cells.
      - Cytologic (Papanicolaou) smears: Neoplastic cells are less cohesive than others--> shed into fluids or secretions
        
        carcinoma of cervix, often at an in situ stage, endometrial carcinoma, bronchogenic carcinoma, bladder and prostate tumors, and gastric carcinomas;
        
        identification of tumor cells in abdominal, pleural, joint, and cerebrospinal fluids
        
        less commonly, for evaluation of other forms of neoplasia
    - - Diagnosis of malignancy: Diagnosis of malignancy:
        
        PCR–based detection of T cell R or Ig genes allows distinction between monoclonal (neoplastic) and polyclonal (reactive) prolifs.
        
        Many hematopoietic neoplasms + a few solid tumors defined by particular translocations ex
        
        FISH or PCR: detect translocations of Ewing sarcoma + several leukemias and lymphomas.
        
        PCR detection of BCR-ABL transcripts in CML
      - Prognosis and behavior:
        FISH + PCR used to detect amplification of oncogenes such as HER2/NEU + NMYC, which provide prognostic and therapeutic info for breast cancers + neuroblastomas
      - Detection of minimal residual disease: detection of BCR-ABL transcripts by PCR in CML. Recognition that virtually all advanced tumors are associated w/ both intact circulating tumor cells + products derived from tumors (tumor DNA) has led to interest in following tumor burden through sensitive blood tests.
      - Diagnosis of hereditary predisposition to cancer: Germline mutation of several tumor suppressor genes, such as BRCA1; detection may allow an aggressive screening protocol, an opportunity for prophylactic surgery, genetic counseling of relatives at risk
      - Therapeutic decision-making
        certain targetable mutations may transgress morphologic categories
        
        تشخیص ژن های خاص در تومورهای مختلف: م ژن BRAF که در بعضی تومورها موتاسیون پیدا میکند ولی این تومورها از نظر مورفولوژیک خیلی باهم متفاوتاند. مثل ملانوم پوست، کارسینوم پاپیلاری تیروئید، langerhans cell histiocytosis ، hairy cell leukemia و آدنوکارسینوم کولون--> یک نوع دارو یعنی داروهای ضد BRAF مثل PLX4032 در تومورهای مختلف استفاده (البته باید اول با روشهای مولکولی تشخیص: این ژن موتاسیون-->این دارو تجویز)
        
        mutations of ALK kinase, originally described in a subset of T cell lymphomas, also identified in a small % of non–small cell carcinomas + neuroblastomas. Clinical trials have shown that lung cancers w/ ALK mutations respond to ALK inhibitors, whereas other lung cancers do not
    - - Expression Profiling: allows simultaneous measurements of expression levels of several thousand genes. In essence, a molecular profile is generated for each tissue analyzed. Such analysis has revealed that phenotypically identical large B cell lymphomas from different patients are heterogeneous w/ respect to their gene expression and survival rates. Similar approaches are now being explored in other cancers, such as breast cancers and melanomas
      - Whole Genome Sequencing: individual tumors can contain from a handful of somatic mutations (certain childhood leukemias) to tens of thousands of mutations, w/ highest mutational burden found in cancers associated w/ mutagen exposure, such as lung cancer and skin cancer. Among these are two types of mutations:
        
        (1) driver mutations: subvert normal control of cell prolif, diff, and homeostasis; could be therapeutic targets;
        generally recurrent + present in a substantial % of patients w/ a particular cancer ex BCR-ABL present in all cases of CML, and fusion pr is an excellent drug target;
        may be present in only a subset of tumors of a particular type ex 4% of non–small cell lung cancers harbor an EML4-ALK tyrosine kinase fusion gene--> patient responds well to ALK inhibitors.
        
        (2) passenger mutations: have no effect on cell phenotype; often much more numerous than driver mutations, most often fall in noncoding regions or have a neutral effect on growth, not conferring any advantage or disadvantage; result from genomic instability; some have important roles in drug resistance ex mutations in BCRABL that confer resistance to imatinib in CML present as passenger mutations in rare clones before therapy begins. bc they confer a powerful selective advantage--> are converted from passengers to drivers in face of drug therapy; it is suspected that the genomic instability of cancer cells sows the seeds of resistance through similar scenarios in many kinds of tumors; some instances, several distinct and relatively uncommon mutations all converge on same pathway (such as resistance to apoptosis) and contribute to the cancer phenotype.
    - - PSA
        
        screen for prostatic adenocarcinoma, often elevated levels in blood; extremely valuable for detecting residual disease or recurrence following treatment
        
        problems: also may be elevated in benign prostatic hyperplasia
        no PSA level that ensures that a patient does not have prostate cancer--> low sensitivity + low specificity.
      - carcinoembryonic Ag (CEA): carcinomas of colon, pancreas, stomach, and breast,
      - alpha fetoprotein: hepatocellular carcinomas, yolk sac remnants in gonads, and occasionally teratocarcinomas + embryonal cell carcinomas.
- - - - In some unusual instances: tumor cells undergo divergent differentiation--> mixed tumors; ex:
        
        mixed tumor of salivary gland: have obvious epith components dispersed throughout a fibromyxoid stroma, sometimes harboring islands of cartilage or bone, thought to derive from epith cells or myoepithelial cells, or both, and preferred designation: pleomorphic adenoma.
        
        Fibroadenoma of female breast: a mixture of prolif ductal elements (adenoma) embedded in a loose fibrous tissue (fibroma). Although only fibrous component is neoplastic
        
        Teratoma: special type of mixed tumor: recognizable mature or immature cells or tissues representative of more than one germ cell layer and sometimes all; originate from totipotential germ cells (normally present in ovary + testis + sometimes abnormally present in sequestered midline embryonic rests)
- - - - suppress host immune responses: TGFβ, secreted in large quantities by many tumors,
      - immune response induced by tumor may inhibit tumor immunity:
        
        recognition of tumor cells --> engagement of T cell inhibitory R, CTLA4, or activation of reg T cells that suppress immune responses.
        
        More insidiously: some express FasL--> engage Fas on immune cell surfaces + induce immune cell to enter apoptosis
  - - - Most tumors express >norm levels +/ abnorm forms of surface GPs + GLs, which may be diagnostic markers and targets for therapy; include gangliosides, blood group Ags, and mucins; most of epitopes recognized by Abs raised against such Ags are not specifically expressed on tumors, they are present at higher levels on cancer cells than normal cells; This class of Ags a target for cancer therapy w/ specific Abs.
      - Several mucins: CA125 and CA199, expressed on ovarian carcinomas, and MUC1, on breast carcinomas. Unlike many other types of mucins, MUC1 is an integral membr pr normally expressed only on apical surface of breast ductal epith, a site relatively sequestered from immune system. In ductal carcinomas of the breast, however, expressed in an unpolarized fashion and contains new, tumor specific carb + peptide epitopes--> induce both antibody + T cell responses--> candidates for tumor vaccines.
    - - In a subset of human melanomas: tyrosinase (involved
        in melanin biosynth expressed only in normal melanocytes and melanomas) T cells from patients w/ melanoma recognize peptides derived from tyrosinase (tyrosinase vaccines may stimulate such responses to melanomas); patients able to respond to a normal self-Ag (tyrosinase normally produced in such small amounts + in so few cells that it is not recognized by immune system and fails to induce tolerance)
      - cancer testis Ags: encoded by genes silent in all normal adult tissues except testis, and deregulated in cancer cells; is present in testis but not expressed on cell surface in an Ag form, bc sperm do not express MHC I--> these Ags are tumors pecific; Prototypical of this group: MAGE (melanoma Ag gene) family of genes. Although tumorspecific, are not unique for individual tumors. MAGE1 is expressed on 37% of melanomas + variable # of lung, liver, stomach, and esophageal carcinomas. Similar Ags called GAGE, BAGE, and RAGE have been detected in other tumors. Several Ags from this category are now being used in tumor vaccine trials.
- - - - (large enough) observed karyotypically more common in nonhematopoietic solid tumors.
      - molecular level commonly found in hematopoietic tumors as well.
    - - ex
        
        HER2/NEU (also known as ERBB2) in 20% of breast cancers, and Ab therapy directed against this R has proved effective
        
        NMYC in 25-30% of neuroblastomas, + poor prognosis
      - chromosomal changes can be identified microscopically. 2 exclusive patterns:
        
        multiple small, extrachromosomal structures “double minutes”
        
        homogeneously staining regions: insertion of amplified genes into new locations (may be distant from normal location); bc regions containing amplified genes lack a normal banding pattern, they appear homogeneous in a Gbanded karyotype
    - - placing oncogenes under control of active promoter--> overexpression
        
        t (8;14) MYC-Ig heavy chain--> Burkitt lymphoma
        
        t (18;14): BCL2--> follicular B cell lymphomas
      - t (22;9) 22: philadelphia-->BCR ABL fusion gene--> chronic myelogenous leukemia + certain acute leukemias;
      - t(11;22)--> fusion EWS-Fli1-->Ewing sarcoma
      - TMPRSS-ETS fusion genes in prostate carcinomas--> inappropriate, androgendependent expression of ETS family transcription factors
- - - - RNA
        
        HTLV1 (only one retrovirus)
        
        a form of T cell leukemia/lymphoma endemic in Japan + Caribbean but sporadic elsewhere; tropism for CD4+ T cells
        transmission of infected T cells through sexual intercourse, blood products, or breastfeeding; Leukemia develops only in 3-5% of infected after a long latent period of 20-50 yrs (suggests a multistep process, during which many oncogenic mutations accumulate)
        
        genome does not contain a viral oncogene + no consistent integration site next to a cellular oncogene; contains a unique region called pX: several genes, including TAX: necessary + sufficient for cellular transformation:
        
        interacts w/ TFs (NFκB)--> transactivate genes encoding cytokines, cytokine Rs, costimulatory molecules--> autocrine signaling loops (IL2, IL2R + (more important) IL15, IL15R)
        
        a parallel paracrine activated by :arrow_up: production of GM-CSF--> stimulates MQs to produce other T cell mitogens
        
        can drive progression by directly binding + activating cyclins.
        
        can repress function of several tumor suppressor genes (CDKN2A/p16 + TP53)
        
        Initially T cell prolif polyclonal bc virus infects many cells, but bc of TAX-based inactivation of tumor suppressor genes-> T cells at :arrow_up: risk for secondary mutations--> outgrowth of a monoclonal neoplastic T population
      - DNA
        
        HPV
        
        types
        
        1, 2, 4, 7: benign squamous papillomas (benign warts: HPV genome maintained in nonintegrated episomal form)
        
        low-risks, predominantly 6,11: Genital warts (low malignant potential)
        
        high-risks, 16, 18, (31?): several cancers (HPV genome randomly integrated into host genome), partic squamous cell carcinoma of cervix + anogenital region; min 20% oropharyngeal cancers, partic those arising in tonsils;
        
        two early viral genes, E6 and E7. (E7/E6 from high-risks has a higher affinity for Rb/p53 than does E7/E6 from low-risks E7/E6)
        
        E7
        
        inactivates CDKIs CDKN1A/p21 + CDNK1B/p27.
        
        binds to Rb--> releases E2F--> cell cycle progression
        
        E6: binds + mediates degradation of p53.
        
        Integration of HPV genome
        
        cells show significantly more genomic instability.
        
        interrupts viral DNA--> overexpression of E6 + E7
        
        However, infection w/ HPV itself not sufficient for carcinogenesis. Cotransfection w/ mutated RAS--> full malignant transformation; multifactorial; primacy of HPV in causation of cervical cancer attested by nearcomplete protection by antiHPV vaccines.
        
        KSHV
        
        سرطان با intermediate malignancy که منشأ آن سلول های عروقی در پوست هستند
        
        در سلولهای اندوتلیال عروق قرار--> تغییراتی در ژنوم--> Kaposi sarcoma که به خصوص در اندام تحتانی مشاهده می شود اما میتواند در جاهای دیگر بدن هم باشد. کاپوسی سارکوما بیشتر در افراد ایدزی و ایمونوساپرسیو اتفاق می افتد و یک تومور عروقی است
        
        HBV, HCV
        
        also contain prs in genomes that may more directly promote the development of cancer.
        
        HBV: a gene known as HBx--> directly / indirectly activate a variety of TFs + several signal transduction pathways; viral integration can cause secondary rearrangements of chromosomes, including multiple deletions that may harbor unknown tumor suppressor genes.
        
        (Although not a DNA virus) HCV: components of genome, such as HCV core pr, may have a direct effect on tumorigenesis, possibly by activating a variety of growth promoting signal transduction pathways.
        
        epidemiologic linking chronic infection w/ hepatocellular carcinoma is strong: 70-85% of hepatocellular carcinomas worldwide are due to infection w/ HBV or HCV.
        
        genomes do not encode any viral oncoprs, and although HBV DNA is integrated within human genome, there is no consistent pattern of integration in liver cells; oncogenic effects are multifactorial, but dominant effect seems to be immunologically mediated chronic inflammation w/ hepatocyte death --> regeneration-->activated immune cells: substances promoting cell survival,.. + other genotoxic + mutagenic mediators--> key molecular step: activation of NFκB pathway in hepatocytes by mediators--> blocks apoptosis,...
        
        EBV: 1st virus linked to a human tumor, Burkitt lymphoma. also: B cell lymphomas in patients w/ defective T cell immunity, a subset of Hodgkin lymphoma, nasopharyngeal carcinoma, a subset of T cell lymphomas, gastric carcinomas, NK cell lymphomas, and even, in rare instances, sarcomas, mainly in immunosuppressed. In immunologically normal persons, EBV-driven polyclonal B prolif controlled--> asymptomatic / self-limited infectious mononucleosis
        
        molecular basis for B cell prolif induced by EBV complex. EBV uses CD21 R to infect B cells--> polyclonal B cell prolif + generation of B lymphoblastoid cell lines; EBV genes:
        
        LMP1 (latent membr pr 1): not expressed in associated Burkitt lymphoma (bc one of major viral Ags recognized by immune system)
        
        activating NFκB + JAK/STAT (mimic B cell activation by CD40)
        
        prevents apoptosis by activating BCL2.
        
        EBNA2: transactivates several host genes (cyclin D + src family of protooncogenes)
        
        viral cytokine, vIL10: pirated from the host genome; can prevent MQs + monocytes from activating T cells and killing virally infected cells.
        
        Burkitt lymphoma: endemic in certain parts of Africa + sporadic elsewhere. In endemic areas, tumor cells in virtually all patients carry EBV genome + concomitant (endemic) malaria (or other infections) impairs immune competence--> sustained B cell prolif; in nonendemic areas: 80% of tumors negative for EBV, but all possess MYC translocations. Lymphoma cells may emerge only when translocations activate MYC, a consistent feature. MYC may substitute for LMP1 signaling, allowing tumor cells to :arrow_down: LMP1 + evade immune system.
        
        In patients w/ deficient T cell function: EBV infected B cells undergo polyclonal expansion, producing lymphoblastoid like cells. In contrast w/ Burkitt lymphoma, B lymphoblasts in immunosuppressed patients do express viral Ags (LMP1) recognized by T cells.
        
        Nasopharyngeal carcinoma endemic in southern China + EBV genome found in all tumors. LMP1 expressed in carcinoma cells and, as in B cells, activates NFκB pathway. Furthermore, LMP1 induces expression of proangiogenic factors which may contribute to oncogenesis.
    - - H.pylori
        
        gastric adenocarcinoma
        
        cause: :arrow_up: epith prolif + chronic inflam background (numerous genotoxic agents, ROS)
        
        histopathologic changes: initial development of chronic inflammation/gastritis--> gastric atrophy-->intestinal metaplasia of lining cells--> dysplasia-->cancer (takes decades + occurs in only 3% of infected)
        
        H. pylori genome: genes directly implicated in oncogenesis. Strains associated w/ gastric adenocarcinoma: a “pathogenicity island” that contains cytotoxin associated A gene (CagA); Although H. pylori noninvasive, CagA is injected into gastric epith--> initiation of a signaling cascade that mimics unregulated GF stimulation,..
        
        gastric lymphomas
        
        B cell origin+ grow in a pattern resembling that of normal MALT (referred to as MALT lymphomas)
        
        molecular pathogenesis: strain specific H. pylori factors + host genetic factors (polymorphisms in promoters of inflam cytokines such as IL1β + TNF)
        
        H. pylori infection--> activation of H. pylori– reactive T cells--> polyclonal B cell prolif--> a monoclonal B cell tumor emerges in prolif B cell (early in course of disease, eradication of H. pylori “cures” lymphoma by removing Ag stimulus for T cells)
  - - - polycyclic hydrocarbons: present in fossil fuels; may be produced from animal fats during broiling meats + present in smoked meats and fish
        
        benzo[a]pyrene formed in high temp combustion of tobacco in cigarette smoking
        
        principal active products in many hydrocarbons: epoxides-->form covalent adducts (addition products) w/ molecules in cell, principally DNA, but also RNA + prs
      - aromatic amines + azo dyes
        
        β naphthylamine was responsible for a 50x incidence of bladder cancers in heavily exposed workers in aniline dye + rubber industries
      - Others: Nitrosamine and amides, Vinyl chloride, nickel, chromium, Insecticides, fungicides, Polychlorinated biphenyls
      - Natural Plant and Microbial Products
        
        HBV: Hepatocellular Carcinoma
        
        Aflatoxin B1 produced by some strains of Aspergillus (grows on improperly stored grains and nuts)--> hepatocellular carcinoma
    - - some are cancer chemotherapy drugs (alkylating agents) in certain types of cancer (Hodgkin lymphoma), only to evoke a subsequent, second form of cancer, u. leukemia.
      - some used for nonneoplastic disorders (RA or Wegener granulomatosis) (associated risk of induced cancer is low)
- - - - “Governors”: classic tumor suppressor genes (RB): mutation--> transformation by removing an important brake on cellular prolif
      - “Guardian”: responsible for sensing genomic damage; some: “damage control response.” (TP53); loss--> :arrow_up: in mutation rate (mutator phenotype)