Cancer

Cohnheim's theory : the theory that tumors develop from embryonic rests which do not participate in the formation of normal surrounding tissue. Ribbert's theory : a tumor is formed from the development of cell rests owing to reduced tension in the surrounding tissues introns harboring translocation breakpoints in tumors are significantly longer than non-translocated introns of the same genes but are not enriched significantly in sequence elements potentially involved in chromosomal rearrangements. DSB, the type of DNA damage that leads to translocations in tumors, are created at random points in the genome, and that sequence elements do not have a widespread role in the localization of these breaksref. initiation : the moment of neoplastic transformation, in which only genotype is alterated (normal morphology); in toxicology, the creation of a small alteration in the genetic makeup of a cell by a low level of exposure to a carcinogen; the cell may later become neoplastic upon repeated exposure to the same carcinogen or exposure to a promoter. inherited susceptibility (Knudson's hypothesisref) : inheritance of a mutated allele (or an allele with hypermethylated CpG islands within promoter : CpG island methylator phenotype (CIMP)) of an oncosuppressor gene (2-10%) => familial cancer (family history of cancer (excluding confounding risk factors), early onset, multifocal, bilateral). E.g. breast carcinoma (mutations in BRCA1) ovary carcinoma familial adenomatous poliposis (FAP) gastric carcinoma (mutations in cadherin E) prostate cancers multiple endocrine neoplasia (MEN) melanoma neurofibromatosis / multiple neuroma / neuromatosis germline epigenetic silencing of MLH1 tumour suppressor leads to colorectal cancersref acquired mutation in a somatic cell => sporadic cancer. It affects more commonly epithelial cells than connective tissue cells as usually the former have a shorter cell cycle (higher proliferation rate) and hence spend proportionally more time with their DNA exposed to noxious stimuli. Unlike rodent cells, which can be transformed with just a couple of oncogenes, human cells are notoriously difficult to transform and require several genetic lesions, including viral oncoproteins such as the SV40 large T and small T antigens, which disrupt both the p53 and RB tumour-suppressor pathways. A combination of just 4 genetic alterations (TERT, HRAS, MYC, and RAS) can transform human diploid fibroblasts leaving the p53 pathway intact : however, as only 5/16 inoculations gave rise to tumours, and the latency was relatively long - 59-98 days - another alteration might have occurred. Although these cells are normally diploid, 2 changes - on chromosomes 18 and 20 - are frequently observedref. Stromal cells exposed to N-nitrosomethylurea (NMU) in vitro can transform normal mammary epithelial cells in vivo, whereas NMU-treated epithelial cells form normal ducts in vivoref. promotion : the entire cell compartment of which the transformed cell is part is stimulated to proliferate (neoplastic hyperplasia) following stimulation by promoting agents, ie chronic exposure to ... growth factors locally produced by inflammatory cells, eg : chronic bronchitis in lung carcinoma chronic cervicitis in cervical carcinoma chronic pancreatitis in pancreatic carcinoma some hormones for hormone-dependent cancers, e.g. : estrogens for ER+ tumors breast adenocarcinoma endometrial carcinoma meningiomas progestins for progesterone receptor+ tumors androgens for AR+prostate adenocarcinoma

tumors grow on average twice as fast in the daily activity phase of the circadian cycle : cancer cells show altered expression of some of their clock genes but retain organization in others. The circadian organization of clock gene expression in normal tissue and sleep activity is not disrupted by tumors. The resulting intratumoral chronic hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Chronic hypoxia also leads to compensatory adaptations, including tumor neoangiogenesis : neovascularization is needed for solid tumors to grow beyond a diameter of 2-3 mm. Tumour-derived PDGFRb+ progenitor perivascular cells (PPCs) have the ability to differentiate into pericytes and regulate vessel stability and vascular survival in tumours. A subset of PDGFRb+ PPCs is recruited from bone marrow to perivascular sites in tumours. Specific inhibition of PDGFR signalling eliminates PDGFRb+ PPCs and mature pericytes around tumour vessels, leading to vascular hyperdilation and endothelial cell apoptosis in pancreatic islet tumours of transgenic Rip1Tag2 miceref. Vasculogenic mimicry : the ability of aggressive tumor cells to express endothelium-associted genes and to form extracellular matrix (ECM)-rich vasculogenic-like networks in 3D culture, as shown by PAS staining. The formation of these networks seems to recapitulate the embryonic development of vasculogenic networks, and are associated with the distinctly patterned, ECM-rich networks that are observed in aggressive tumours of patients with cancer. Some of these channellike spaces were originally known as "vascular channels", because they were found to contain erythrocytes and plasma. They were thought to provide a mechanism of perfusion and a dissemination route within the tumour that functioned either independently of or simultaneously with angiogenesis (or other sources of vascularization such as vessel co-option). There is viable blood flow between tumour cell-lined vascular spaces and endothelium-lined and/or mature vasculatureref. Even tumor cells have anticoagulant properties similar to endothelial cells and there is an exchange of blood from the normal vasculature (blood vessels) at the periphery of the tumor through tumor-cell-lined extravascular spaces within the aggressive tumor. Vasculogenic mimicry has been seen in melanomaref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10 (individuals with melanomas that have undergone vasculogenic mimicry have a poor prognosis), breast carcinomaref1, ref2, ref3, ref4, prostatic carcinomaref1, ref2, ovarian carcinomaref1, ref2, non-small cell lung carcinomaref, Drosophila (large tumour suppressor gene, lats-negative) tumoursref, synoviosarcomaref, rhabdomyosarcomaref, pheochromocytomaref, cytotrophoblasts forming the placentaref1, ref2. Blood lakes are areas of hemorrhages generally lacking an endothelial-cell lining that are often seen in histological sections of high-grade neoplasms. The meshwork may provide a nutritional exchange for aggressive tumors that might prevent cell death within the tumor : anyway centers in the middle ot the tumor undergo necrosis, creating the cancer or intratumoral abscess, eventually infected by anaerobic bacteria (Bacteroides fragilisref). Compared with normal blood vessels, tumour vasculature is extremely leaky and this aids tumour progression, as plasma proteins can enter the surrounding tissue to provide a fertile environment for tumour growth. Plugging the leaks in tumour blood vessels with cavtratin (a chimeric peprtide containing the scaffolding domain of caveolin-1 - which inhibits VEGF-induced eNOS activation and reduces expression of PECAM-1 and Flt-4 / VEGFR3- linked to a cellular internalization sequence) blocks tumour growth. Stimulators of angiogenesis : tumor-angiogenesis factor (TAF) : a factor produced by cancer cells of solid tumors that stimulates the growth of blood vessels into the tumor. HUAF = FGF-1 / aFGF + FGF-2 / bFGF + ESAF RNPs TGF-a and TGF-b angiogenin

Cu2+-heparin TNF-a thymosin-b4 either directly or by increasing VEGF expression - and by promoting cell migration, which might be due to its actin-binding functionref EPHB4 reverse signalling though ephrin B2 is involved in blood-vessel growth during development and promotes tumor angiogenesisref the enzymatic activity of COX-2 is critical for the induction of angiogenesis at least in colorectal cancers and breast cancers : PGE2 stimulates the expression of angiogenic regulatory genes. HIF-1a loss of HIF-1a results in increased tumour progression in highly vascularized tissues where tumours can hijack preexisting normal blood vessels to grow : loss of VEGF slows growth of these tumours by impairing survival of the hijacked vasculature. increased HIF-1a levels are found in many human cancers and are associated with ... increased mortality : early stage cervical cancerref, radiation-treated cervical cancerref, LN-positiveref or LN-negativerefbreast cancers, oligodendrogliomaref, oropharyngeal squamous cell carcinoma (SCC) (also radiation resistance)ref, ovarian cancer (with p53)ref, early stage oesophageal cancer (resistance to PDT with BCL2)ref, endometrial cancerref, head and neck SCCs (HIF-2a)ref, and GIST of stomachref decreased mortality : head and neck SCCs status post-surgeryref increased or decreased mortality : NSCLCref1, ref2 effects of altered HIF-1 activity on tumour growth monitored by xenograft in nude mice : m cell type manipulation rate of tumour growth tumour angiogenesis growth or survival of cells cultured under conditions of hypoxia or O2/glucose deprivation ex vivo decreased HIF-1 activity Hepa1 mouse hepatomaref1, ref2 HIF1b LOF - - mouse ESref HIF-1a KO - - mouse ESref HIF-1a KO + - + MEF (T-Ag, HRASV12)ref1, ref2 HIF-1a KO - 0 HCT116, MDA-MB-435ref HIF-1a transactivation domain (TAD) - - PCI-43 (pancreatic CA)ref HIF-1a DN - 0 MEF (T-Ag, HRASV12)ref Hif-1a KO, chemo - ND 5 human cancer cell linesref YC-1 i.p. - - ND increased HIF-1 activity HCT116 (colon CA)ref HIF-1a GOF + + ND PCI-10 (pancreatic CA)ref HIF-1a GOF + 0 + 786-O/VHLref HIF-2a (P531A) + + ND 786-O/VHLref HIF-1a ODD + ND ND mouse ESref Vhl KO - + ND The tumor cells produce FGF-2 / bFGF, VEGF, and PD-ECGF, and in turn the tumor endothelium produces PDGF, IGF-1, FGF-2 / bFGF, HB-EGF, G-CSF, and IL-6 for the cancer cells. b-defensin-29 expressed by murine tumor cells recruits bone marrow– derive DC precursors to tumors : Vegf-A expressed by the same tumor cells induces their endothelial-like specialization and migration to vessels of tumorinfiltrating DCs, which independently assemble neovasculature in vivoref. Tumour xenografts and spontaneously arising tumours respond in different ways to angiogenic stressref1, ref2. Tumor lymphangiogenesisalso may accompany tumor growth and may facilitate tumor metastasis to lymph nodes : some experiments revealed no signs of lymphangiogenesis within tumors as pressure gradients can prevent dyes injected into cancers from entering the tumoral lymphatics. Fluid pressure in tumors enlarges the lymphatics in the margin, and these hyperplastic lymphatic vessels can facilitate metastasis : even lymphatics incapable of fluid transport can serve as conduits of tumor cells. Alternatively VEGF-C and VEGF-D binding to Flt-4 /

VEGFR-3 might increase metastasis by inducing lymphatic endothelial cells (LECs) to produce chemokines, which, in turn, may induce the directional migration of tumor cells into preexisting or newly formed lymphatics. Another possibility is that VEGF-C and VEGF-D might alter the adhesive capacity of LECs in a way that permits tumor cells to move into lymphatics.