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Lodish H, Berk A, Zipursky SL, et al. Molecular cabinet Biology. 4th edition. Brand-new York: W. H. Freeman; 2000.
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Although much research right into the molecular communication of cancer makes use of cells growing inculture, us need first to think about tumors as they occur in experimental pets andin humans. In this way we deserve to see the gross nature of thedisease — the properties that at some point must beexplained by analysis of genes and also cells.
Metastatic Tumor Cells space Invasive and Can Spread
Tumors arise with good frequency, especially in older animals and also humans, butmost pose little risk to your host since they are localized and also of smallsize. We contact such tumors benign;an instance is warts. That is usually obvious when a tumor is benign due to the fact that itcontains cells that closely resemble, and also may duty like, normal cells. Thesurface communication molecules that organize tissues together store benign tumorcells, like normal cells, localized to proper tissues. Benign liver tumorsstay in the liver, and also benign minister tumors continue to be in the intestine. A fibrouscapsule usually delineates the extent of a light tumor and also makes that an easytarget for a surgeon (Figure 24-1).Benign tumors become serious medical troubles only if their sheer bulkinterferes with normal attributes or if they secrete excess quantities ofbiologically active substances prefer hormones.
Sections that two species of light tumors. (a) A tumor derived from cells that secrete neuroendocrine hormones.It is arranged like a tiny gland in the middle of common tissue.(b) A rectal epithelial tumor seen below as invaginations into thenormal smooth (more...)
In contrast, the cells creating a malignant tumor, or cancer, express part proteins properties ofthe cell kind from which that arose, and a high fraction of the cells grow anddivide much more rapidly than normal. Some malignant tumors stay localized andencapsulated, at least for a time; an instance is carcinoma in situ in the ovaryor breast. Most, however, execute not stay in their original site; instead, theyinvade bordering tissues, get into the body’s circulatory system,and set up locations of proliferation far from the website of their originalappearance. The spread out of tumor cells and also establishment of second areas ofgrowth is referred to as metastasis; mostmalignant cells eventually acquire the ability to metastasize. Therefore the majorcharacteristics that distinguish metastatic (or malignant) tumors from benignones room their invasiveness and spread.
Cancer cells can be distinguished from typical cells by microscope examination.They room usually much less well identified than normal cells or benign tumorcells. Liver cancers, because that instance, express some of but not all the proteinscharacteristic of normal liver cells and also may eventually evolve to a state inwhich they lack most liver-specific functions. In a particular tissue, malignantcells typically exhibit the attributes of rapidly farming cells, that is, ahigh nucleus-to-cytoplasm ratio, prominent nucleoli, numerous mitoses, andrelatively little dedicated structure. The visibility of invading cell in anotherwise normal tissue ar is the most diagnostic point out of amalignancy (Figure 24-2).
Gross and microscopic views of a tumor invading typical livertissue. (a) The gun morphology that a human liver in i m sorry a metastatic lungtumor is growing. The white protrusions on the surface of the liverare the tumor masses. (b) A light micrograph (more...)
Malignant cells usually retain sufficient resemblance come the typical cell form fromwhich castle arose, together judged through morphology and by expression the cell-specificgenes, the it is possible to classify lock by their relationship to normaltissue. Normal pet cells are often classified according to their embryonictissue of origin, and also the naming of tumors has complied with suit. Cancers take place inmost types of cells; compared with the 300 or therefore different types of cell in thehuman body, we have the right to recognize 200 different species of human cancers. Malignanttumors room classified together carcinomasif they derive from endoderm or ectoderm and also sarcomas if they derive from mesoderm. The leukemias, a class of sarcomas, growas individual cells in the blood, whereas most other tumors room solid masses.(The surname leukemia is derived from the Latin for“white blood”: the huge proliferation the leukemic cellscan reason a patient’s blood to appear milky.)
Alterations in Cell-to-Cell interactions Are associated withMalignancy
The border of a typical cell type to a offered organ or organization is kept bycell-to-cell recognition and by physical barriers. Primary amongst the physicalbarriers that keep tissues separated is the basal lamina (also called the basementmembrane), i beg your pardon underlies layers of epithelial cells too assurrounds the endothelial cell of blood ship (see figures 15-23 and also 22-21). Basal laminae specify the surface of external and also internalepithelia and the framework of blood vessels.
Metastatic cell break your contacts with various other cells in their tissue of originand get over the limit on cell movement provided by basal laminae andother barriers. As a result, metastatic cells can go into the circulation andestablish us in one more site remote from their original location. Inthe procedure of metastasizing, they may attack adjoining tissue prior to spreadingto far-off sites through the circulation. Both these occasions require breach that abasal lamina.
Tumor cells often develop elevated level of cell-surface receptors particular forthe proteins and also polysaccharides writing basal laminae (e.g., collagens,proteoglycans, and also glycosaminoglycans) and also secrete enzymes that digest theseproteins. Many tumor cells likewise secrete a protease referred to as plasminogenactivator, i beg your pardon cleaves a peptide shortcut in the serum proteinplasminogen, convert it come the energetic proteaseplasmin. Cheap of a tiny amount the plasminogenactivator causes a big increase in protease concentration by catalyticallyactivating the plentiful plasminogen in common serum. This raised proteaseactivity disclosure metastasis by help tumor cell digest and penetrate thebasal lamina. The normally invasive extraembryonic cell of the fetus secreteplasminogen activator as soon as they are implanting in the uterine wall, a compellinganalogy to intrusion by tumor cells. As the basal lamina disintegrates, sometumor cell will go into the blood, however fewer than 1 in 10,000 cells that escapethe major tumor survive to colonize an additional tissue and form a secondary,metastatic tumor (see number 24-2). Sucha cell very first must adhere to an endothelial cell lining a capillary and migrateacross or through it right into the basic tissue. To set up a metastasis, a tumorcell must have the ability to multiply there is no a fixed of surrounding identical cells andto adhere to brand-new types of cells. The wide range of altered behaviors thatunderlie malignancy may have their basis in brand-new or variant surface ar proteins madeby malignant cells.
Tumor development Requires development of new Blood Vessels
Tumors, whether main or secondary, call for recruitment of new blood vessels inorder to thrive to a huge mass. In the lack of a blood supply, a tumor cangrow right into a mass of about 106 cells, around a sphere 2 mm indiameter. In ~ this point, division of cells on the external of the tumor mass isbalanced by death of those in the center due to an poor supply ofnutrients. Such tumors, uneven they secrete hormones, cause few problems.However, most tumors induce the formation of new blood vessels that attack thetumor and also nourish it, a process called angiogenesis. Althoughthis complicated process is not construed in detail, it can be described as severaldiscrete steps: destruction of the basal lamina the surrounds a nearbycapillary, migration of endothelial cells lining the capillary into the tumor,division of this endothelial cells, and also formation that a new basement membranearound the freshly elongated capillary.
Many tumors produce growth components that wake up angiogenesis; various other tumorssomehow induce surrounding normal cells to synthesize and secrete such factors.Basic fibroblast expansion factor (bFGF), transforming growth factor α(TGFα), and also vascular endothelial development factor (VEGF), which aresecreted by many tumors, all have angiogenic properties. Brand-new blood vesselsnourish the growing tumor, enabling it to rise in size and also thus boost theprobability that additional harmful mutations will occur. The presence of anadjacent blood vessel additionally facilitates the procedure of metastasis.
One that the many mysterious aspects of angiogenesis is the a major tumor willoften secrete a substance the inhibits angiogenesis around secondarymetastases. In this case, operation removal that the primary tumor may stimulategrowth the its metastatic an additional tumors. Several organic proteins the inhibitangiogenesis (e.g., angiogenin and endostatin) or antagonists that the VEGFreceptor have actually excited much interest as therapeutic agents due to the fact that they can beuseful versus many kinds of tumors. While new blood vessels room constantlyforming throughout embryonic development, couple of form normally in adults; thus aspecific inhibitor that angiogenesis can have couple of adverse next effects.
DNA native Tumor Cells can Transform typical Cultured Cells
The morphology and growth nature of tumor cells clearly differ native those oftheir normal counterparts. That mutations cause these differences wasconclusively created by transfection experiments through a heat of culturedmouse fibroblasts called 3T3 cells. This cells normally grow only as soon as attachedto the plastic surface of a culture dish and are maintained at a low celldensity. Due to the fact that 3T3 cell stop farming when they call other cells, theyeventually kind a monolayer the well-ordered cells that have actually stoppedproliferating and are in the G0 step of the cabinet cycle (Figure 24-3a). Back suchquiescent cell in a saturated culture have stoppedgrowing, they remain viable because that a long time and also can resume development if castle arereleased from call inhibition and listed with development factors present inserum. As is true for various other cultured fibroblasts, the precise cell form that givesrise to 3T3 cells is uncertain, however they can identify into a range ofmesodermally obtained cell types, especially fat cells and endothelial cells(those that line blood vessels).
Scanning electron micrographs that normal and transformed 3T3cells. (a) common 3T3 cells room elongated and are aligned and closely packedin an orderly fashion. (b) 3T3 cells transformed by thev-src oncogene encoded by Rous sarcoma virus.The cells room (more...)
When DNA native a person bladder carcinoma, computer mouse sarcoma, or various other tumor is addedto a society of 3T3 cells, around one cabinet in a million incorporates a particularsegment of bladder carcinoma DNA that causes a distinctive phenotype. Theprogeny that the impacted cell are more rounded and less adherent to one anotherand come the dish than room the normal neighboring cells, forming athree-dimensional cluster of cells (a focus) that can be well-known under themicroscope (Figure 24-3b). Together cells,which continue to thrive when the typical cells have end up being quiescent, haveundergone change and aresaid to it is in transformed. Revolutionized cells have countless propertiessimilar to those the the cells composing malignant tumors, including changes incell morphology, capacity to grow unattached come a basal lamina or otherextracellular matrix, lessened requirement for expansion factors, cheap ofplasminogen activator, and also loss that actin microfilaments.
Figure 24-4 outlines the procedure fortransforming 3T3 cells through DNA indigenous a human being bladder carcinoma and also cloning thespecific DNA segment that reasons transformation. Succeeding studies verified thatthe copy segment contained a mutant version of the cellularras gene, designated rasD.Normal Ras protein, which participates in many intracellular signal transductionpathways triggered by expansion factors, cycles in between an inactive,“off” state through bound GDP and an active,“on” state through bound GTP (see figure 20-22). Due to the fact that the mutated RasDprotein hydrolyzes bound GTP really slowly, it accumulates in the active state,sending a growth-promoting signal to the nucleus even in the absence of thehormones normally forced to activate theRas – MAP kinase pathway (see figure 20-28).
The identification and also molecular cloning of the rasDoncogene. Enhancement of DNA native a human bladder carcinoma to a culture of mouse3T3 cell causes around one cabinet in a million to division abnormallyand kind a focus, or clone of transformed cells. Come clone (more...)
Expression that the RasD protein, however, is not enough to causetransformation of common cells in a primary culture of human, rat, or mousefibroblasts. Unlike cells in a main culture, however, cultured 3T3 cell haveundergone a loss-of-function mutation in the p16 gene; asdiscussed later, the p16 gene encodes a cyclin-kinase inhibitorthat restricts development through the cabinet cycle. Together cells deserve to growindefinitely if regular diluted and supplied v nutrients. Transformationof these cells calls for both lose of p16 and also expression of aconstitutively active Ras protein; for this reason, transfection through therasD gene have the right to transform 3T3 cells but not normalcultured primary fibroblast cells.
A mutant ras gene is found in most human colon, bladder, andother cancers, but not in normal human being DNA; for this reason it must arise together the result ofa somatic mutation in among the tumor progenitor cells. Any gene, together asrasD or v-src, that encodes aprotein qualified of transforming cells in culture or inducing cancer in animalsis described as an oncogene. Thenormal moving gene native which it occurs is dubbed a proto-oncogene.
Development the a Cancer needs Several Mutations
Conversion that a typical body cell into a malignant one is now recognized to requiremultiple mutations. Three different species of experimental approaches allconverged top top this crucial conclusion: epidemiology of human cancers, analysesof DNA in cells at several stages in the breakthrough of cancers in human beings andmice, and also overexpression that oncogenes in cultured cells and transgenicanimals.
Each individual cancer is a clone the arises native a single cell. Assuming that the price ofmutation is roughly consistent during a lifetime, then the incidence of mosttypes of cancer would be elevation of period if only one mutation wererequired to convert a common cell into a malignant one. In fact, however,the incidence that most varieties of human cancers rises markedly andexponentially with period (Figure24-5). Although many explanations that this phenomenon have beenconsidered, the incidence data are most regular with the concept thatmultiple mutations are forced for a cancer to form.
The incidence of several person cancers boosts markedlywith age. Keep in mind that the logarithm of annual incidence is plotted matches thelogarithm that age.
According come this “multi-hit” model, cancers arise by aprocess that clonal an option not uneven the selection of separation, personal, instance animalsin a huge population. A mutation in one cell would give it a slim growthadvantage. One of the progeny cells would certainly then undergo a 2nd mutationthat would permit its descendants to grow more uncontrollably and form asmall bright tumor; a 3rd mutation in a cell within this tumor would certainly allowit to outgrow the others, and also its progeny would kind a mass of cells, eachof which would have actually these 3 mutations. An additional mutation in one ofthese cell would enable its progeny come escape into the blood and establishdaughter swarms at various other sites, the hallmark that metastatic cancer. Sincedecades are required for this multiple mutations come occur, the exponentialincrease in cancer incidence with period is guess by the multi-hit version ofcancer induction.
Somatic Mutations in human being Tumors
Surgeons deserve to produce relatively pure samples of plenty of human cancers, yet generallythe cell that provide rise to these tumors can not be identified and also analyzed.An exemption is colon cancer, i m sorry evolves through distinct,well-characterized morphological stages (Figure 24-6). Because these intermediatestages — polyps, light adenomas, andcarcinomas — can be isolated through a surgeon,mutations that take place in every of the morphological stages can be identified.These studies have established a collection of mutations that generally arise in awelldefined order, providing strong support for the multi-hit model.Invariably the first step in colon carcinogenesis requires loss the afunctional APC gene; however, no every colon canceracquires every the later on mutations or acquires them in the very same order.
The advance and metastasis of human being colorectal cancer andits genetic basis. A mutation in the APC tumor-suppressor gene in asingle epithelial cell reasons the cell to divide, althoughsurrounding cells perform not, creating a fixed of localized benigntumor (more...)
Polyps are precancerous growths on the inside of the colon wall. Most of thecells in a polyp save the very same one or two mutations in theAPC gene that an outcome in its ns or inactivation; thusthey space clones of cell in i beg your pardon the original mutations occurred.APC is one of numerous tumor-suppressor genes, many of which encode proteinsthat inhibit the development of certain types of cells with the cell cycle. APC does so by inhibiting the capacity of the Wntprotein to activate expression that the myc gene. The absence of functionalAPC protein therefore leads to unreasonable activation that Myc, a transcription aspect that cause expression of many genes forced for the transitionfrom the G1 come the S step of the cell cycle. Both alleles of theAPC gene must lug an inactivating mutation because that polypsto form, since cells through one wild-type APC gene expressenough APC protein to function normally. Persons end 50 year of age arenow recommend to have actually a regular colonoscopy, a procedure because that scanning thewall of the colon. Any type of polyps that are present can be gotten rid of easily. Sincepolyps regularly evolve (or “progress”) into a benign andthen a metastatic tumor, the identification and also removal that polyps oftenprevents advancement of colon cancer.
If among the cell in a polyp undergoes one more mutation, this time anactivating mutation in the ras gene, its progeny divide inan even an ext uncontrolled fashion, creating a larger adenoma (see number 24-6). Mutational lose ofanother tumor-suppressor gene, designated DCC, followed byinactivation that the p53 gene, outcomes in a malignantcarcinoma. DNA from different human colon carcinomas usually containsmutations in all these genes — APC,p53, K-ras, andDCC — establishing thatmultiple mutations in the very same cell are essential for the cancer come form. Someof this mutations show up to confer growth advantages at very early stage oftumor development, whereas various other mutations encourage the later stages,including degradation of the basal lamina, i beg your pardon is forced for themalignant phenotype.
Inherited Mutations That rise Cancer Risk
Most colon cancer patients have two regular APC alleles intheir germ-line DNA, denote that 2 somatic mutations, one in eachAPC allele, must have developed in a solitary colonepithelial cell. However, in individuals who inherit a germ-line mutation inone APC allele, somatic ns or mutation of only the oneremaining functional APC allele, fairly than two, isrequired because that a polyp to form. Countless precancerous polyps construct inthese individuals; because there is a really high probability the one or moreof these polyps will progress to malignancy, together individuals have a greatlyincreased risk for arising colon cancer before the age of 50.
As we detail below, individuals with inherited mutations in othertumor-suppressor genes have a hereditary prejudice forcertain cancers. Such people inherit a germ-line mutation in one alleleof the gene; somatic mutation of the second allele facilitates tumorprogression. Although together cancers, which constitute around 10 percent ofhuman cancers, are described as inherited, the inherited,germ-line mutation alone is not enough to cause tumordevelopment. The inherited forms of plenty of cancers space clinically comparable tothe noninherited kind but occur earlier in life and often are marked byformation of multiple primary tumors, fairly than a single one.
Overexpression the Oncogenes
Overexpression the Myc protein is associated with many species of cancers, a notunexpected finding, due to the fact that this transcription variable stimulates expression ofmany genes forced for cell-cycle progression. But overexpression that Myc intransgenic mouse is insufficient to induce tumor formation; other oncogenicmutations additionally must occur. This “cooperativity” ofoncogenic mutations has been displayed most dramatically in transgenic micecarrying both the myc gene and the mutantrasD gene moved by a mammarycell – specific promoter/enhancer indigenous aretrovirus (Figure 24-7). By itself,a myc transgene causes tumors just after 100 days, and also thenin just a couple of mice; plainly only a minute fraction of the mammary cell thatoverexpress the Myc protein become malignant. Expression that the mutantRasD protein alone reasons tumors earlier but still slowly andwith around 50 percent efficiency over 150 days. As soon as the myc andrasD transgenics room crossed, however, such the all mammarycells refer both Myc and RasD, tumors to happen much more rapidlyand all animals succumb come cancer. Such experiments emphasize thesynergistic results of lot of oncogenes. They also suggest that the longlatency that tumor formation, even in the double-transgenic mice, is due tothe should acquire extr somatic mutations.
Kinetics that tumor illustration in female transgenic micecarrying transgenes pushed by the computer mouse mammary tumor virus(MMTV) breast-specific promoter. Displayed are outcomes for mice delivering either myc orrasD transgenes and forthe progeny the a cross (more...)
Similar participating effects can be watched in cultured cells. When normal cellsare inserted in tool with low amounts of growth factors such asplatelet-derived expansion factor (PDGF) or epidermal development factor (EGF), theybecome clogged in the G0 or G1 phase of the cell cyclebut stay viable. Recombinant cells that overexpress Myc also arrest theirgrowth under this conditions, however soon experience apoptosis, or programmed cell fatality (Chapter 23). Reportedly the cell“senses” the is receiving one inappropriate“growth” signal indigenous Myc in the absence of other“growth signals” from surface ar receptors and commitssuicide. However, overexpression of Bcl-2, a protein the inhibitsapoptosis, rescues this Myc-overexpressing cell from death. As aconsequence, a cell the overexpresses both the Myc and Bcl-2 proteins canproliferate in the absence of normal expansion factors. Consistent with thesecell society studies, overexpression that both Myc and Bcl-2 protein isfrequently uncovered in human leukemias and also lymphomas.
Cancers Originate in Proliferating Cells
In order because that oncogenic mutations come induce cancer, lock must happen in dividingcells so that the mutations are passed ~ above to plenty of progeny cells. Once suchmutations happen in nondividing cell (e.g., neurons and also muscle cells), theygenerally execute not induce cancer, i beg your pardon is why tumors that muscle and nerve cellsare rare in adults. Nonetheless, cancer wake up in plenty of tissues created ofnondividing identified cells such as erythrocytes and also most white bloodcells, absorptive cells the line the small intestine, and keratinized cellsthat kind the skin. Return such differentiated cells cannot divide, they arecontinually replaced by differentiation that stem cells. This procedure is the crucial to understanding how cancersarise in these tissues.
Stem cell are qualified of regenerating a certain tissue because that the life of anorganism. Lock are thought about self-renewing in that some of their daughtersbecome stem cells. Unipotent stem cells offer rise to just asingle identified cell type, conversely, pluripotent stem cellscan distinguish into number of cell types that perform committed functions(see number 14-7). The hematopoieticsystem offers a well-studied instance of pluripotent stem cells. Because that example,hematopoietic stem cells deserve to be purified from bone marrow v a fluorescentactivated cell sorter (see number 5-21).This sorting depends on the presence of certain cell-surface protein thatdistinguish hematopoietic stem and progenitor cell from other cell species andthe absence on stem cells of various other cell-surface proteins that are characteristicof distinguished hematopoietic cells. Every of the surface proteins binds adifferent monoclonal antibody, tagged through a different fluorescent dye, and also thusFACS can separate those cells with particular combinations of cabinet surfaceproteins. As soon as purified stem cells room injected right into a computer mouse whose stem cellshave been damaged by whole-body gamma irradiation, the injected cells giverise to all the various species of blood cells. A comparable approach is supplied totreat leukemia and also breast cancer in humans: bone marrow or purified stem cellsare injected into patients first subjected to lethal sheep of radiation orcytotoxic drugs in bespeak to death the tumor cells and normal stemcells.
Detailed studies have actually elucidated the hematopoietic pathway presented in number 24-8. Under suitable conditions,stem cells in the bone marrow division to form two varieties of cells: another stem cell and a lineage-committed progenitor cell. The last cellssometimes are described as burstforming devices (BFUs) andcolony-forming systems (CFUs) since after dividing severalmore times, each develops a clone (i.e., a colony) of distinguished cells.Numerous extracellular factors, referred to as cytokines, are vital for formation of lineage-committedprogenitors and the subsequent proliferation and differentiation of these cells.Many of these cytokines space secreted through stromal cells in the bone marrow or areon the surface ar of these cells. Some, like SCF, IL-3, or GM-CSF, support theproliferation and also differentiation that progenitors for many blood cabinet types.Others, prefer Epo, exert their principal activity on progenitors of a singlelineage. In the lack of an important cytokine, a progenitor cell undergoesapoptosis. Thus hematopoietic progenitor cells deserve to undergo one of two fates:they deserve to die, or lock can give rise come a clone of a specific form ofdifferentiated blood cell. Once created in the bone marrow, distinguished bloodcells enter the circulation.
Formation of distinguished blood cells from hematopoietic stemcells in the bone marrow. Pluripotent stem cells (dark red) may either self-renew or give riseto myeloid and lymphoid stem cell (light red). Although this stemcells maintain the capacity (more...)
Stem cells exist in other tissues, such together intestine, liver, skin, bone, andmuscle; they provide rise to all or plenty of of the cell types in these tissues,replacing age cells, by pathways analogous come hematopoiesis in bone marrow.Because stem cell divide consistently over the life of an organism, generatingadditional stem cells, oncogenic mutations in your DNA have the right to accumulate,eventually transforming them right into cancer cells. Cells that have got thesemutations have an abnormal proliferative capacity however generally cannot undergonormal procedures of differentiation. Countless oncogenic mutations, such together ones thatprevent apoptosis or create an unreasonable growth-promoting signal, additionally canoccur in an ext differentiated yet still replicating progenitor cells. Suchmutations in hematopoietic progenitor cells have the right to lead to various species ofleukemia. Likewise, colon cancer occurs from mutations in proliferating cellsthat continuous are generated to change worn-out epithelial cells lining thecolon.
In humans, the kinetics that the figure of tumors suggests that many differentmutational events conspire with each other to cause cancer. Ours longevity family member tothat of mice, because that instance, suggests that the human types has progressed multipleways to counter the propensity of cell to accumulate mutations, so the humancells have protections the rodent cell either lack or have actually in a less efficientform. Prefer the continual battle that we bring out with the transmittable agentsthat surround us, we additionally are continuous battling the tendency of cells tobecome transformed into cancer cells.
Both main and second tumors requireangiogenesis, the recruitment of brand-new blood vessels, in stimulate to thrive toa huge mass.
Cancer cells, which are closer in theirproperties to stem cells 보다 to much more mature differentiated cell types,usually arise indigenous stem cells and also other proliferating cells.
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