WHAT IS NEOPLASIA ?

NEOPLASIA
Retno Murwanti DVM, MSc, PhD Faculty of Pharmacy Gadjah Mada University 2012

The pathological process that results in the formation and growth of a neoplasm or tumor. neoplasm, tumor, cancer

CANCER

The hallmark of cancer

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Figure 1. Acquired Capabilities of Cancer We suggest that most if not all cancers have acquired the same set various mechanistic strategies.

of functional during their development, albeit through Distinctive andcapabilities complementary capabilities that enable tumor growth and metastatic dissemination

We describe each capability in turn below, illustrate with a few examples its functional importance, and indicate strategies by which it is acquired in human cancers.

Acquired GS autonomy was the first of the six capabilities to be clearly defined by cancer researchers, in large part because of the prevalence of dominant oncogenes that have been found to modulate it. Three common Figure 3. Emerging Hallmarks and En Characteristics molecular strategies for achieving autonomy are eviAn increasing body of research suggests t dent, involving alteration of extracellular growth signals, additional hallmarks of cancer are involve pathogenesis of some and perhaps all c of transcellular transducers of those signals, or of intraOne involves the capability to modify, or cellular circuits that translate those signals into action. gram, cellular metabolism in order to mos tively support neoplastic proliferation. The While most soluble mitogenic growth factors (GFs) are allows cancer cells to evade immuno made by one cell type in order to stimulate proliferation destruction, in particular by T and B lymph macrophages, and natural killer cells. B of anotherthe process of heterotypic signalingmany neither capability is yet generalized and fu cancer cells acquire the ability to synthesize GFs to dated, they are labeled as emerging hal Additionally, two consequential characteri which they are responsive, creating a positive feedback neoplasia facilitate acquisition of both co signaling loop often termed autocrine stimulation (Fedi emerging hallmarks. Genomic instability a mutability endow cancer cells with geneti et al., 1997). Clearly, the manufacture of a GF by a cancer ations that drive tumor progression. Inam cell obviates dependence on GFs from other cells within by innate immune cells designed to ght inf and heal wounds can instead result in the the tissue. The production of PDGF (platelet-derived vertent support of multiple hallmark capa growth factor) and TGF (tumor growth factor ) by thereby manifesting the now widely appr tumor-promoting consequences of inam glioblastomas and sarcomas, respectively, are two illusresponses. trative examples (Fedi et al., 1997). The cell surface receptors that transduce growthstimulatory signals into the cell interior are themselves targets of deregulation during tumor pathogenesis. GF receptors, often carrying kinase in extraordinary ability of genome maintenance syste Yet other distinct attributes of tyrosine cancer cells have activities been The Cell 144, March 4, 2011 proposed to be functionally importantare for the development ofin detect and resolve defects in the DNA ensures that ra their cytoplasmic domains, overexpressed many cancer and might therefore be added to the list of core enable hallmarks mutation are usually very low during eac cancers. Receptor overexpression may thespontaneous can(Negrini et al., 2010; Luo et al., 2009; Colotta et al., 2009). Two generation. In the course of acquiring the roster of mutant cer cell to become hyperresponsive to ambient levels such attributes are particularly compelling. The rst involves needed to orchestrate tumorigenesis, cancer cells of GF that normally would not trigger proliferation (Fedi major reprogramming of cellular energy metabolism in order to increase the rates of mutation (Negrini et al., 2010; Salk et al., 1997). cell Forgrowth example, the epidermal GF receptor support continuous and proliferation, replacing the 2010). This mutability is achieved through increased sen (EGF-R/ erbB )that is operates upregulated stomach, brain,toand metabolic program in mostin normal tissues and mutagenic agents, through a breakdown in one or s fuels the physiological operations the associated cells. The components of the genomic maintenance machinery, or breast tumors, while the of HER2/ neu receptor is overexsecond involves evasion by mammary cancer cells from attack and In addition, the accumulation of mutations can be accele pressed inactive stomach and carcinomas (Slamon elimination by immune cells;and this capability highlights the dichot- gross by compromising the surveillance systems that normally m et al., 1987; Yarden Ullrich, 1988). Additionally, omous roles of an immune system that both antagonizes and genomic integrity and force genetically damaged cells into overexpression of GF receptors can elicit ligand-indeenhances tumor development and progression. Both of these senescence or apoptosis (Jackson and Bartek, 2009; K pendent signaling (DiFiore et al., Ligand-indepencapabilities may well prove to facilitate the1987). development and 2008; Sigal and Rotter, 2000). The role of TP53 is centra dent signaling can also be achieved through structural

PATHOPHYSIOLOGY OF NEOPLASIA
Why it is important?
diagnosis (type, stages, prognosis) development of anti-cancer drugs

THE MOLECULAR AND CELLULAR BASIS OF NEOPLASIA

THE MOLECULAR AND CELLULAR BASIS OF NEOPLASIA

GENETIC CHANGES IN NEOPLASIA

Tumor oncogene : gene that has the potential to cause cancer

a spectrum of diseases characterized by abnormal growth and invasion of cells a result of stepwise alterations in cellular function : proliferative, invasive, and metastatic potential Etiology : epigenetic changes environment

Tumor suppressor genes : a gene whose function is to limit cell proliferation and loss of whose function leads to cell transformation and tumor growth. Proto-oncogenes : a normal gene that with slight alteration by mutation or other mechanism becomes an oncogene Inactivation of tumor suppressor genes : frame-shift mutation, deletion of part or all of the gene, and gene silencing by way of promoter methylation. Activation of proto-oncogenes : mutation, gene amplication and overexpression, chromosomal translocation, and possibly other mechanisms.

PROTO-ONCOGENES & TUMOR SUPPRESSOR GENES IN NORMAL PHYSIOLOGY & NEOPLASIA

Protein encoded by proto-oncogene and tumor suppressor gene : recognize and repair DNA damage regulate the cell cycle, mediate growth factor signal transduction pathways regulate programmed cell death, involved in cell adhesion proteolytic proteins, and transcription factors Advantages of Mutations to tumors : increased genomic instability, elimination of cell cycle checkpoints, inactivation of programmed cell death (apoptotic) pathways, increased growth factor signaling, decreased cell adhesion increased extracellular proteolysis.

REPRESENTATIVE ONCOGENES ACTIVATED IN HUMAN TUMORS.

Oncogene EGFR/HER1 HER2/Neu Cyclin D1 K-ras, N-ras, Hras Src Myc B-Raf Cellular function Growth factor receptor Growth factor receptor Cell cycle regulator G protein, signal transductions Signal transduction Transcription Factor Signal Transduction Tumor Types Activated Glioblastoma, lung and breast cancer Breast, ovarian, gastric cancer
Breast and esophageal cancer, lymphoma, parathyroid adenoma

Mechanism of Action Mutation, amplication Amplication Amplication, translocation Mutation Mutation Mutation, amplication Mutation

Multiple tumors types Multiple tumor types, melanomas Multiple tumors types Multiple tumor types, melanomas

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REPRESENTATIVE TUMOR SUPPRESSOR GENES INACTIVATED IN HUMAN TUMORS.

Tumor Tumor Suppressor Suppressor Gene Gene
p53! Rb! APC! PTEN! hMLH1 BRCA1! BRCA2! WT-1! Cell cycle regulator Cell cycle regulator Cell adhesion Signal transduction, adhesion signaling DNA mismatch repair DNA ds-break repair DNA ds-break repair Transcription factor

Changes in gene expression

Tumor Types Inactivated

Multiple tumor types Retinoblastoma, small cell lung cancer, sarcoma Colon cancer Glioblastomas, prostate cancer, breast cancer Colon cancer, melanoma Breast and ovarian cancers Breast and ovarian cancers Wilms' tumor

Mechanism of Inactivation
Mutation Deletion, mutation Deletion, mutation Deletion, mutation Mutation Mutation Mutation Deletion, mutation

Hereditary Syndromes with a Germ-line Inactivated Allele

Li-Fraumeni Familial retinoblastoma Familial adenomatous polyposis Cowden's Hereditary nonpolyposis colon cancer Familial breast/ovarian Familial breast/ovarian Childhood Wilms' tumor Cell 144, March 4, 2011
Figure 2. Intracellular Signaling Networks Regulate the Operations of the Cancer Cell
An elaborate integrated circuit operates within normal cells and is reprogrammed to regulate hallmark capabilities within cancer cells. Separate subcircuits, depicted here in differently colored elds, are specialized to orchestrate the various capabilities. At one level, this depiction is simplistic, as there is considerable crosstalk between such subcircuits. In addition, because each cancer cell is exposed to a complex mixture of signals from its microenvironment, each of these subcircuits is connected with signals originating from other cells in the tumor microenvironment, as outlined in Figure 5.

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The Cells of the Tumor Microenvironment

Figure 4. The Cells of the Tumor Microenvironment
(Upper) An assemblage of distinct cell types constitutes most solid tumors. Both the parenchyma and stroma of tumors contain distinct cell types and subtypes that collectively enable tumor growth and progression. Notably, the immune inammatory cells present in tumors can include both tumor-promoting as well as tumor-killing subclasses. (Lower) The distinctive microenvironments of tumors. The multiple stromal cell types create a succession of tumor microenvironments that change as tumors invade normal tissue and thereafter seed and colonize distant tissues. The abundance, histologic organization, and phenotypic characteristics of the stromal cell types, as well as of the extracellular matrix (hatched background), evolve during progression, thereby enabling primary, invasive, and then metastatic growth. The surrounding normal cells of the primary and metastatic sites, shown only schematically, likely also affect the character of the various neoplastic microenvironments. (Not shown are the premalignant stages in tumorigenesis, which also have distinctive microenvironments that are created by the abundance and characteristics of the assembled cells.)

HORMONES, GROWTH FACTORS, & OTHER CELLULAR GENES IN NEOPLASIA

Key mediators of neoplasia : altered genes (oncogenes or tumor suppressor genes) Another essential component of normal regulation : the system of hormones, growth factors, and growth inhibitors Inuence : mitogenesis, growth inhibition, changes in cell cycle regulation, apoptosis, differentiation, and induction of a secondary set of genes transforming growth factor- (TGF-), estrogen receptor (ER), androgen receptor (AR)

often-rare tumor-initiating cells proved to share transcriptional proles with certain normal tissue stem cell populations, motivating their designation as stem-like. Cell 144, March 4, 2011 The origins of CSCs within a solid tumor have not been claried and indeed may well vary from have been portrayed as reasonably homogeneous cell popula- one tumor type to another. In some tumors, normal tissue stem tions until relatively late in the course of tumor progression, cells may serve as the cells-of-origin that undergo oncogenic when hyperproliferation combined with increased genetic transformation to yield CSCs; in others, partially differentiated instability spawn distinct clonal subpopulations. Reecting transit-amplifying cells, also termed progenitor cells, may suffer such clonal heterogeneity, many human tumors are histopatho- the initial oncogenic transformation thereafter assuming more logically diverse, containing regions demarcated by various stem-like character. Once primary tumors have formed, the degrees of differentiation, proliferation, vascularity, inamma- CSCs, like their normal counterparts, may self-renew as well tion, and/or invasiveness. In recent years, however, evidence as spawn more differentiated derivatives; in the case of has accumulated pointing to the existence of a new dimension neoplastic CSCs, these descendant cells form the great bulk of of intratumor heterogeneity and a hitherto-unappreciated many tumors. It remains to be established whether multiple subclass of neoplastic cells within tumors, termed cancer stem distinct classes of increasingly neoplastic stem cells form during cells (CSCs). inception and subsequent multistep progression of tumors, ultiAlthough the evidence is still fragmentary, CSCs may prove to mately yielding the CSCs that have been described in fully develbe a common constituent of many if not most tumors, albeit oped cancers. being present with widely varying abundance. CSCs are dened Recent research has interrelated the acquisition of CSC traits ECM : operationally Extra Cellular Matrix to maintain architectural framework tissues through their ability to efciently seed new tumors with the of EMT transdifferentiation program discussed above upon inoculation into recipient host mice (Cho and Clarke, 2008; (Singh and Settleman, 2010; Mani et al., 2008; Morel et al., ProteinLobo families to constitute the ECM : to embed cells within the ECM, to attach et al., 2007). This functional denition is often comple- 2008). Induction of this program in certain model systems can cells tomented each other, and to reestablish the ECM when necessary. by including the dissolve expressionand in CSCs of markers that induce many of the dening features of stem cells, including are also expressed by the normal stem cells in the tissue-of- self-renewal ability and the antigenic phenotypes associated Abnormalities of these proteins frequently occur in later stages of normal tumorigenesis, with both and cancer stem cells. This concordance origin (Al-Hajj et al., 2003). account for the loss of architecture, and mediate the invasive andthat metastatic CSCs were initially implicated in the pathogenesis of hematosuggests the EMT program not only may enable cancer cells poietic malignancies (Reya et al., 2001; Bonnet and Dick, 1997) to physically disseminate from primary tumors but also can phenotype of tumor cells and then years later were identied in solid tumors, in particular confer on such cells the self-renewal capability that is crucial breast carcinomas and neuroectodermal tumors (Gilbertson and toECM their subsequent clonal expansion Integrins : a large family of membrane proteins that bind ligands, anchor cells at sites of dissemination Rich, 2007; Al-Hajj et al., 2003). Fractionation of cancer cells on (Brabletz et al., 2005). If generalized, this connection raises an to the ECM, and activate intracellular signaling pathways in response to ECM signals. the basis of displayed cell-surface markers has yielded subpop- important corollary hypothesis: the heterotypic signals that Tumor ulations cells can reshufe their expression proles in favor of an invasive of neoplastic cells with integrin a greatly enhanced ability, rela- trigger an EMT, such as those or released by an activated, inamtive to the corresponding majority populations, to seed new matory stroma, may also be important in creating and maintainmetastatic phenotype. tumors upon implantation in immunodecient mice. These ing CSCs.

STROMAL, ADHESIVE, & PROTEOLYTIC PROTEINS

Signaling Interactions in the Tumor Microenvironment during Malignant Progression

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Cadherins are a family of membrane proteins that function in epithelial cell-to-cell adhesion.
662 Cell 144, March 4, 2011 2011 Elsevier Inc.

Matrix metalloprotease family and the serine protease family.

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Signaling Interactions in the Tumor Microenvironment during Malignant Progression

ALTERATIONS IN METABOLISM & OXYGENATION IN NEOPLASIA

Abnormalities in cancer : cell proliferation and survival, signal transduction, adhesion, and migration, tumor cells have changes in metabolic pathways in order to meet their increased metabolic requirements. Oxygen pressure is reduced hypoxia signals expression for adaptation to the hypoxic environment. changes in gene

Angiogenic growth factors: signal the proliferation of vascular structures into tumor tissue for nutrition and oxygenation. Vascular endothelial growth factor (VEGF), a mitogen to endothelial cells secreted by tumor cells and activates the VEGF receptors in endothelial cells, leading to de novo vascularization. Although most cells may not ordinarily express VEGF, malignant transformation often results in the induction of VEGF expression by tumor cells, either directly through the effects of oncogenes or the loss of tumor suppressor genes or indirectly as a result of hypoxia and the induction of hypoxia-induced gene transcription.
Figure 5. Signaling Interactions in the Tumor Microenvironment during Malignant Progression
(Upper) The assembly and collective contributions of the assorted cell types constituting the tumor microenvironment are orchestrated and maintained by reciprocal heterotypic signaling interactions, of which only a few are illustrated. Cell 144, March 4, 2011 (Lower) The intracellular signaling depicted in the upper panel within the tumor microenvironment is not static but instead changes during tumor progression as a result of reciprocal signaling interactions between cancer cells of the parenchyma and stromal cells that convey the increasingly aggressive phenotypes that underlie growth, invasion, and metastatic dissemination. Importantly, the predisposition to spawn metastatic lesions can begin early, being inuenced by the differentiation program of the normal cell-of-origin or by initiating oncogenic lesions. Certain organ sites (sometimes referred to as fertile soil or metastatic niches) can be especially permissive for metastatic seeding and colonization by certain types of cancer cells, as a consequence of local properties that are either intrinsic to the normal tissue or induced at a distance by systemic actions of primary tumors. Cancer stem cells may be variably involved in some or all of the different stages of primary tumorigenesis and metastasis.

Other growth factors also have proangiogenic effects : epidermal growth factor, broblast growth factor, transforming growth factor-, and others.

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Phenotypic Changes in the Progression of Neoplasia

1. Genomic instability
!!Impaired DNA repair !!Autonomous growth !!Abnormalities of cell cycle control !!Exaggerated response to hormonal or growth factor stimuli !!Lack of response to growth inhibitors or cell contact inhibition !!Aberrant cell cycle checkpoint control !!Antigen modulation and masking !!Elaboration of immune response antagonistic molecules !!Attachment to extracellular matrix !!Secretion of proteolytic enzymes !!Recruitment of stromal cells to produce proteolytic enzymes !!Loss of cell cohesion !!Enhanced cell motility !!Recognition of endothelial protein sequences !!Cytoskeletal modications !!Cell adhesion and attachment !!Tissue-specic tropism

CELLULAR CHANGES IN NEOPLASIA

2. Enhanced proliferation

3. Evasion of immune system

Cancer stem cells :cells that are capable of self-renewal and of generating daughter cells that can proliferate much faster and produce new tumors. Current efforts explore the hypotheses : defects in normal tissue stem cells within an organ give rise to cancer stem cells and terminally differentiated cells (non-stem cells) modied the machinery used by normal stem cells in the process of becoming cancer stem cells.

4. Invasion of tissue and stroma

5. Ability to gain access to and from lymphatics and bloodstream 6. Establishment of metastatic foci 7. Ability to recruit vascularization to support growth of primary or metastatic tumor

Altered drug metabolism and drug inactivation

8. Drug resistance

!!Increased synthesis of targeted enzymes !!Enhanced drug efux !!Enhanced DNA damage repair

CLASSIFICATION OF NEOPLASIA

CLASSIFICATION OF NEOPLASIA

Carcinoma : originate from ectodermal or endodermal tissues the most common cancer type and include all the common epithelial tissue cancers such as lung, colon, breast, and prostate cancers. Sarcoma : originate from mesodermal tissues arise from mesenchymal cell types, which are predominantly the connective tissues. Malignancies of blood cells, including leukemias and lymphomas, are technically a subtype of sarcomas because they are of mesenchymal origin

CLASSIFICATION OF NEOPLASIA

EPITHELIAL NEOPLASMA

Epithelial neoplasia Mesenchymal, Neuroendocrine, Germ Cell Neoplasia Hematologic Neoplasms

carcinoma in situ carcinoma

invasive carcinoma

metastatic

Colon carcinoma, Breast cancer, Lung cancer

Schematic depiction of phenotypic transition of epithelial cells from hyperplasia to invasive carcinoma

MESENCHYMAL, NEUROENDOCRINE, GERM CELL NEOPLASIA

Early childhood, young adulthood
such as muscle or cartilage. Nuclear pleomorphism and mitotic rate determine the grade of a tumor; a higher grade correlates with a higher propensity to invade local and distant structures and a poorer survival. Sarcomas also have a tendency to retain the cell appearance and repertoire of expressed proteins of the cell of origin. Bone matrix of calcium and phosphorus can form within osteosarcomas, and calcification of these tumors can be observed on radiography. There is less of a propensity for direct tissue invasion by sarcomas than by epithelial malignancies. However, tissue destruction can result when a sarcoma compresses but does not invade adjacent tissue, leading to the formation of a pseudocapsule. Sarcomas exhibit metastatic dissemination to regional lymph nodes and distant organs, especially the lungs. High-grade histologic features and anatomic location are factors influencing the likelihood and timing of metastases.

Various genetic these abnormalities have been detected in sarcomas. Mutations in the p53 tumormore suppressor gene are the most commonly Because cells are actively dividing and subject to detected lesion, although such changes are also seen in epithelial neoplasms. The NF1 tumor suppressor gene was originally identified through a germline mutation of this gene in patients with type 1 neurofibromatosis. This inherited syndrome is characterized by caf-au-lait mutational events hyperpigmented skin spots and multiple benign neurofibromas (benign tumors of Schwann cells) under the skin and throughout the body. protein-signaling pathways. Given the complex of cellular activities governed by G protein-mediated pathways, the mechanisms by to These tumor types mayset not evolve in specic anatomic sites due which NF1 abnormalities contribute to the malignant phenotype are not fully understood. the extensive migration and convolution of embryonic cell layers Checkpoint 27. From what two kinds of locations do sarcomas arise? during early development 28. What kinds of sarcomas are more common in children? 30. To what sites do sarcomas commonly metastasize? Sarcoma, Carcinoid tumors, testicular germ cell cancer, 31. What is the most common genetic lesion in sarcomas? neuroblastoma, teratoma 32. What are the characteristics of type 1 neurofibromatosis, and what is a likely molecular basis for the development of neoplasia in this syndrome? 29. Are sarcomas more or less likely to directly invade tissues compared with epithelial malignancies? These can degenerate into malignant neurofibrosarcomas (malignant malignant schwannoma schwannoma). NF1 mutations have since been detected in sporadic sarcomas of different types. Defective or absent activity of the NF1 protein is known to cause enhanced activation of the

Hematologic Neoplasms
Hematologic neoplasms are malignancies of cells derived from hematopoietic precursors. The true hematopoietic stem cell has the capacity for self-renewal and the ability to give rise to precursors (colony-forming colony-forming units units) that proliferate and terminally differentiate toward one of any lineage (Figure 5 3). Distinct hematologic neoplasms can arise from each of the mature cell types. Many of these arise in the bone marrow, circulate in the bloodstream, and can infiltrate certain organs and tissues. Others may form tumors in lymphoid tissue, particularly lymphomas, which arise from lymphoblasts. The lineage of a hematopoietic cell and the degree of differentiation along that lineage are associated with the cell surface expression of characteristic proteins, many of which are receptors, others are adhesion molecules and proteases, and some are of unknown function. These clusters of differentiation (CD) antigens have become essential diagnostic tools in the management of hematologic neoplasms, and some types of malignancies are defined by characteristic CD expression patterns.

Schematic depiction of phenotypic transition of epithelial cells from hyperplasia to invasive carcinoma.

From a pathophysiologic standpoint, certain structural and functional characteristics must be acquired by malignant cells, as outlined in Table 5 4. An increase in growth rate through several mechanisms has been described for different tumor types. It is known that the proliferative fraction (the percentage of cells in S phase, or actively synthesizing DNA) is elevated, and more so in histologically and

HEMATOLOGIC NEOPLASMS

clinically aggressive tumors. Changes in the tightly regulated cell cycle machinery have been observed, including abnormal levels of cyclins and other proteins that regulate cyclin-dependent kinases responsible for entry of the cell into S phase. Likewise, alterations of intermediate signaling proteins have been noted that couple external growth factor and hormonal stimuli to proliferation. The to migrate and pass through cellular and ECM barriers can be enhanced in tumor cells. This can occur through the activation of proteolyticenzyme cascades from within the tumor cell or by the action of stromal cells that are directed to do so as a result of factors produced by nearby tumor cells. Through similar mechanisms, malignant cells can induce the formation of a microvasculature that is essential to support the continued growth of a tumor colony. Other functions necessary to breach the immune defenses and survive destruction by antitumor drugs can be mediated by the genetic program already possessed in latent form by tumor cells. Examples include modulation of antigens and alterations in drug metabolism or metabolic pathways that are targeted by certain drugs.

Classication of leukemias according to cell type and lineage.

Figure 5 3

Malignancies of cells derived from hematopoietic precursors.

Table 5 4 Phenotypic Changes in the Progression of Neoplasia.

The true hematopoietic stem cell has the capacity for self-renewal and the ability to give rise to precursors (colony-forming units) that proliferate and terminally differentiate toward one of any lineage.

1. Genomic instability

2. Enhanced proliferation Autonomous growth

Distinct hematologic neoplasms can arise from each of the mature cell types: in the bone marrow, circulate in the bloodstream, and can Aberrant cell cycle checkpoint control inltrate certain organs and tissues.
Impaired DNA repair Abnormalities of cell cycle control

Exaggerated response to hormonal or growth factor stimuli

Others may form tumors in lymphoid tissue, particularly lymphomas, which arise from lymphoblasts.

Lack of response to growth inhibitors or cell contact inhibition 3. Evasion of immune system Antigen modulation and masking Elaboration of immune response antagonistic molecules 4. Invasion of tissue and stroma
Chandrasoma P, Taylor CE. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright 1998
Classification of leukemias according to cell type and lineage. (Redrawn, with permission, from Chandrasoma P, Taylor CE. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright 1998 by the Hill Companies, Inc.)

DIRECT SYSTEMIC EFFECTS OF NEOPLASMS.

Effect
Vessel compression

Clinical Syndrome
Edema, superior vena cava syndrome Bleeding Lymphedema Pain, numbness, dysesthesia
Weakness, numbness, headache, coordination and gait abnormalities, visual changes

SYSTEMIC EFFECT OF NEOPLASIA

Vessel invasion and erosion Lymphatic invasion Nerve invasion Brain metastases Spinal cord compression Bone invasion and destruction Bowel obstruction and perforation Airway obstruction Ureteral obstruction Liver invasion and metastases Lung and pleural metastases Bone marrow inltration

Pain, paralysis, incontinence Pain, fracture Nausea, vomiting, pain, ileus Dyspnea, pneumonia, lung volume loss Renal failure, urinary infection Hepatic insufciency Dyspnea, chest pain Pancytopenia, infection, bleeding

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Therapeutic Targeting of the Hallmarks of Cancer

Questions
1.What stepwise phenotype changes are the hallmarks of cancer? 2.What is an oncogene? 3.What is a tumor suppressor gene? 4.What are the genetic mechanisms by which oncogenes can be activated or tumor suppressor genes inactivated? 5.Which is the more common mechanism of oncogene inactivation in humans: viral infection or somatic alteration? 6.What is a cancer stem cell? 7.Name some factors that support or inhibit tumor growth but are not directly implicated in tumorigenesis. 8.Give some examples of early, middle, and late changes in the progression of neoplasia.

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Figure 6. Therapeutic Targeting of the Hallmarks of Cancer
Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use in treating certain forms of human cancer. Additionally, the investigational drugs are being developed to target each of the enabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs listed are but illustrative examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallmarks.