Transcript Tumor

Introduction to Cancer
1. Cancer Incidence and Mortality
2. What Is Cancer
3.History of Cancer Research
1. Cancer Incidence and Mortality
Cancer is a leading disease, cause of death, and source of morbidity in the world.
 WHO国际癌症研究机构IARC《2014年世界癌症报告》:
全球癌症发病率与死亡率持续上升：
•2012年当年1400万人被诊断患癌、800万死于癌症；
•预测2035年癌症新患者将增至2400万、1460万人死于癌症。
2012年发病率前三名癌症: 肺癌(180万)、乳癌(170万)、大肠癌(140万)。
死亡率前三名癌症：肺癌、肝癌、胃癌。
在发展中国家，超过22%死亡由传染性病原体相关癌症造成，例如由乙型和丙型病毒性肝炎引
起的肝癌、由人乳头状瘤病毒感染导致的宫颈癌，以及由幽门螺旋菌导致的胃癌等。
2012年，全球新病例有一半发生在亚洲，其中大部分发生在中国。
Ferlay J SI, Ervik M, Dikshit R, et al. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide:
IARC Cancer Base No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013.
[cited 2014 Jul 31]. Available from: http://globocan.iarc.fr.
中国肿瘤登记中心《2012中国肿瘤登记年报》
《中国癌症防治三年行动计划（2015-2017年）》（国家卫计委，教育部等）
每年新发肿瘤病例约312万例，每天约8550人;
每年因癌死亡270万例,居民因癌死亡率13%，即每7-8人中有1人因癌死亡。
恶性肿瘤发病:第一位肺癌，其次胃癌、结直肠癌、肝癌和食管癌;
恶性肿瘤死亡：第一位肺癌，其次肝癌、胃癌、食管癌和结直肠癌；
中国近20年来癌症呈现年轻化及发病率和死亡率“三线”走高趋势。
致癌因素主要包括:慢性感染、不健康的生活方式、环境污染和职业暴露等;
我国癌谱兼具发展中国家与发达国家癌谱特征，一段时期内以肝癌、胃癌、食管癌、
宫颈癌为主的发展中国家癌谱,和以肺癌、乳腺癌、结直肠癌为主的发达国家癌谱将
在我国并存.
2. What is cancer?
Tumor: Benign, Malignant
Carcinogensis is multistep process, involving the multiple genetic and /or epigenetic
changes, leading to the activation of oncogenes and the inactivation of tumor
suppressors in cells.
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Current concept of cancer
3. History of Cancer Research
Kiberstis P, Marshall E. Cancer crusade at 40. Celebrating an anniversary. Introduction. Science. 2011;331(6024):1539.
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大数据 Big data
免疫治疗 Immunotherapy
精准治疗 Precision medicine
Genetic and epigenetic
alterations in cancer
1. Genetic Basis of Cancer
2. Beyond Genetics: The role of Epigenetics
3. Outside Influences
4. Hallmarks of cancer
1. The Genetic Basis of Cancer
 Cancer associated genetic mutations are most often found in:
proto-oncogenes and tumor suppressor genes.
 These genes normally regulate the natural processes of cell fate to keep
tissues and organs healthy.
 Genome-Based Medicine in Oncology
Introduction to Special Issue: Cancer Genomics:
Zahn LM, Travis J. Cancer genomics. A medical renaissance? Introduction.
Science. 2013;339(6127):1539
(1) Exploring the Genomes of Cancer Cells
Michael R. Stratton. Exploring the Genomes of Cancer Cells: Progress and Promise. Science 331, 1553 (2011).
(2) Large-Scale Genomic Initiatives
Several coordinated efforts to exploit whole genome sequencing to identify the
genetic mutations in different cancer types and subtypes.
The data generated by these initiatives are already reshaping our definition of
cancer: cancer is a group of diseases defined not only by the anatomical site from
which they originate, but also by the genetic alterations that are driving their
formation.
This new knowledge is rapidly advancing precision medicine.
 The Cancer Genome Atlas (TCGA):
NCI and the National Human Genome Research Institute (NHGRI) launched
TCGA (cancergenome.nih.gov) in 2006.
charting the genomic changes in more than 20 types or subtypes of cancer.
For each form of cancer being studied, tumor and normal tissues from hundreds
of patients are analyzed.
TCGA database: Data generated through TCGA are freely available and widely
used by the cancer research community.
 International Cancer Genome Consortium (ICGC)
Launched in 2008, the ICGC (icgc.org) comprises research groups around the
world, including some from TCGA.
To harmonize the many large-scale genomic projects underway by generating,
using, and making freely available common standards of data collection and
analysis.
To identify the genetic changes in 50 different types or subtypes of cancer, and it
currently has 53 project teams studying more than 25,000 tumor genomes. For
each form of cancer being studied, tumor and normal tissues from approximately
500 patients are analyzed.
Data generated by ICGC project teams are freely available and widely used by
the cancer research community.
 St. Jude Children’s Research Hospital–Washington University Pediatric
Cancer Genome Project (PCGP)
in 2010 to sequence the genomes of both normal and cancer cells from more than
600 children with cancer.
The PCGP (pediatriccancergenomeproject.org) is the largest investment to date
aimed at understanding the genetic origins of childhood cancers.
(3) Cancer Genome Landscapes
[Vogelstein B, et al. Cancer Genome Landscapes. Science, 2013, 339:1546]
Comprehensive sequencing efforts have revealed the genomic landscapes of
common forms of human cancer.
For most cancer types, this landscape consists of a small number of “mountains”
(genes altered in a high percentage of tumors) and a much larger number of “hills”
(genes altered infrequently).
These studies have revealed ~140 genes that, when altered by intragenic
mutations, can promote or “drive” tumorigenesis.
A typical tumor contains two to eight of these “driver gene” mutations; the
remaining mutations are passengers that confer no selective growth advantage.
Driver genes can be classified into 12 signaling pathways that regulate three core
cellular processes: cell fate, cell survival, and genome maintenance.
Drive genes: increasing the selective growth advantage of tumor cells.
Mut-driver genes contain a sufficient number or type of driver gene mutations.
Epi-driver genes are expressed aberrantly in tumors through changes in DNA
methylation or chromatin modification that persist as the tumor cell divides
 Tumors contain large numbers of epigenetic changes affecting DNA or chromatin
proteins. For example, more than 10% of the protein-coding genes in CRC were
differentially methylated when compared with normal colorectal epithelial cells.
 Some of these changes in Epi-driver genes provide a selective growth advantage. For
example, epigenetic silencing of CDK2NA and MLH1 is much more common than
mutational inactivation in these two driver genes
Difference between a genetic and an epigenetic change in a gene.
Unlike the sequence of a gene in a given individual, methylation is plastic,
varying with cell type, developmental stage, and patient age.
Epigenetic modification can change under microenvironmental cues, such as
low nutrient concentrations or abnormal cell contacts.
It is difficult to know whether specific epigenetic changes observed in cancer
cells reflect, rather than contribute to, the neoplastic state.
Criteria for distinguishing epigenetic changes that exert a selective growth
advantage from those that do not (passenger epigenetic changes) have not yet
been formulated.
How Many Genes Are Mutated in a Typical Cancer?
Number of somatic mutations in representative human cancers, detected by
genomewide sequencing studies. Numbers in parentheses indicate the median number of
nonsynonymous mutations per tumor in a variety of tumor types .
When do these mutations occur?
Genetic alterations and the progression of colorectal cancer.
Tumors evolve from benign to malignant lesions by acquiring a series of mutations over time,
a process that has been particularly well studied in colorectal tumors
The major signaling pathways that drive tumorigenesis are shown at the transitions between
each tumor stage. One of several driver genes that encode components of these pathways can
be altered in any individual tumor. Patient age indicates the time intervals during which the
driver genes are usually mutated. Note that this model may not apply to all tumor types.
From a genetics perspective, it would seem that there must be mutations that convert a
primary cancer to a metastatic one, just as there are mutations that convert a normal cell to a
benign tumor, or a benign tumor to a malignant one.
Despite intensive effort, consistent genetic alterations that distinguish cancers that
metastasize from cancers that have not yet metastasized remain to be identified.
 Other Types of Genetic Alterations in Tumors
Most solid tumors display widespread changes in
chromosome number (aneuploidy), deletions,
inversions, translocations, and other genetic
abnormalities
Protein-coding genes account for only ~1.5% of
the total genome, and the number of alterations in
noncoding regions is proportionately higher than
the number affecting coding regions. The vast
majority of the alterations in noncoding regions are
presumably passengers.
(4) Signaling pathways and cellular processes
involved in cancer
The immense complexity of cancer genomes is somewhat misleading. After all,
even advanced tumors are not completely out of control.
>99.9% of the alterations in tumors are immaterial to neoplasia(including point
mutations, copy-number alterations, translocations, and epigenetic changes
distributed throughout the genome, not just in the coding regions). They are simply
passenger changes that mark the time that has elapsed between successive clonal
expansions.
Normal cells also undergo genetic alterations as they divide, both at the nucleotide and
chromosomal levels. However, they are programmed to undergo cell death in response to
such alterations as a protective mechanism.
Cancer cells have evolved to tolerate genome complexity by acquiring mutations in
genes such as TP53. Thus, genomic complexity is, in part, the result of cancer, rather
than the cause.
There is order in cancer. Mutations in driver genes do one thing: cause a selective
growth advantage, either directly or indirectly.
All of the known driver genes can be classified into 12 signaling pathways. These
pathways can be organized into three core cellular processes.
 A sequential series of alterations in well-defined
genes that alter the function of a limited number of
pathways. A common and limited set of driver genes
and pathways is responsible for most common forms
of cancer.
 These genes and pathways offer distinct
potential for early diagnosis: the genes
themselves, the proteins encoded by these genes,
and the end products of their pathways are, in
principle, detectable in many ways:
 Analyses of relevant body fluids: urine for
genitourinary cancers, sputum for lung cancers, and
stool for gastrointestinal cancers.
 Molecular imaging: the presence, location and extent
of cancer.
Cancer genome sequencing has an
impact on the clinical care of cancer
patients.
The recognition that certain tumors
contain activating mutations in driver
genes encoding protein kinases has led to
the development of small-molecule
inhibitor drugs targeting those kinases.
Two representative pathways (RAS and
PI3K):
• Red: proteins encoded by the driver
genes.
• Yellow balls: sites of phosphorylation.
• Examples of therapeutic agents.
Tumor related signaling pathways
 Intracellular Signaling Networks Regulate the Operations of the Cancer Cell.
An integrated circuit operates within normal cells and is reprogrammed to regulate hallmark
capabilities within cancer cells.
Separate subcircuits (in differently colored fields) orchestrate the various capabilities.
There is considerable crosstalk between subcircuits.
Each of these subcircuits is connected with signals originating from other cells in the tumor
microenvironment.
(5) Genetic Heterogeneity
Four types of genetic heterogeneity in tumors
illustrated by a primary tumor in the pancreas and its metastatic lesions in the liver. Mutations introduced
during primary tumor cell growth result in clonal heterogeneity. A typical tumor is represented by cells
with a large fraction of the total mutations (founder cells) from which subclones are derived. The
differently colored regions in the subclones represent stages of evolution within a subclone.
(A) Intratumoral: heterogeneity among the cells of the primary tumor. (B) Intermetastatic: heterogeneity
among different metastatic lesions in the same patient. In the case illustrated here, each metastasis was
derived from a different subclone. (C) Intrametastatic: heterogeneity among the cells of each metastasis
develops as the metastases grow. (D) Interpatient: heterogeneity among the tumors of different patients.
The mutations in the founder cells of the tumors of these two patients are almost completely distinct.
Cancer is not a unified and static unit. Each cancer could be considered an
evolutionary experiment involving a genetically plastic population of cells
undergoing selection within a tumor.
The genomic composition of single cells in an individual cancer before and
after treatment may best uncover the genetic fluxes that lead to therapeutic
resistance.
(EDISON T. LIU. EDITORIAL: Grappling with Cancer. Science 29 March 2013: 1493.)
2. Beyond Genetics: The role of Epigenetics
 Each cell in an individual contains the same 25,000 genes. Natural differences in genome
accessibility lead to the diverse array of cell types in our bodies.
 Special chemical marks on DNA and histones together determine genome accessibility, and
thus gene usage, in a given cell type. The sum of these epigenetic marks is referred to as the
epigenome.
 Epigenetic defects in conjunction with permanent changes in the genetic material of the
cell promote cancerous behaviors.
In addition to specific genetic mutations that result in aberrant proteins driving some forms
of cancers, changes in the chemical tags on DNA, or on histones, as well as mutations within
the proteins that read, write, or erase these tags, can also lead to cancer.
 Some epigenetic abnormalities are reversible. Epigenetic Therapies (The FDA approved):
 DNA methylation inhibitors: azacitidine (Vidaza) and decitabine (Dacogen) for the
treatment of myelodysplastic syndrome(MDS).
 Histone deacetylase inhibitors: romidepsin (Istodax) and vorinostat (Zolinza) for the
treatment of certain lymphomas. In July 2014, the FDA approved belinostat (Beleodaq),
which targets multiple types of histone deacetylases, for the treatment of patients with
peripheral T-cell lymphoma who had become resistant to or had relapsed on prior therapies.
(1) Cancer epigenetics: From mechanism to therapy
(Dawson MA, Kouzarides T. Cancer epigenetics: From mechanism to therapy. Cell.2012;150:12).
 Epigenetics is most commonly used to describe chromatin-based events that
regulate DNA-templated processes, such as transcription, DNA repair, and
replication.
 DNA methylation, histone modification, nucleosome remodeling, and RNAmediated targeting regulate many biological processes that are fundamental to the
genesis of cancer.
 Complexity and plasticity.
 Basic principles behind these epigenetic pathways
 Their misregulation in cancer.
 Epigenetic drugs against chromatin regulators.
 There are at least four different DNA modifications and 16 classes of histone modifications
 Cancer Mutations Affecting Epigenetic Regulators of DNA Methylation.
The 5-carbon of cytosine nucleotides are methylated (5mC) by a family of DNMTs. One of
these, DNMT3A, is mutated in AML, myeloproliferative diseases (MPD), and myelodysplastic
syndromes (MDS). In addition to its catalytic activity, DNMT3A has a chromatin-reader motif,
the PWWP domain, which may aid in localizing this enzyme to chromatin. Somatically
acquired mutations in cancer may also affect this domain.
The TET family of DNA hydroxylases metabolizes 5mC into several oxidative intermediates,
including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine
(5caC). These intermediates are likely involved in the process of active DNA demethylation.
Two of the three TET family members are mutated in cancers, including AML, MPD, MDS,
and CMML.
Mutation types:
M, missense;
F, frameshift;
N, nonsense;
S, splice site mutation;
T, translocation.
 Cancer Mutations Affecting Epigenetic Regulators of Histone Acetylation
Somatic cancer-associated mutations in
histone acetyltransferases and proteins that
contain bromodomains (which recognize and
bind acetylated histones).
Several histone acetyltransferases possess
chromatin-reader motifs; mutations in the
proteins may alter both their catalytic
activities as well as the ability of these
proteins to scaffold multiprotein complexes
to chromatin.
Sequencing of cancer genomes to date has
not identified any recurrent somatic
mutations in histone deacetylase enzymes.
(Abbreviations:
AML, acute myeloid leukemia; ALL, acute lymphoid
leukemia; B-NHL, B-cell non-Hodgkin’s lymphoma;
DLBCL, diffuse large B-cell lymphoma; and TCC,
transitional cell carcinoma of the urinary bladder)
 Cancer Mutations Affecting Epigenetic Regulators of Histone Methylation
Recurrent mutations in histone methyltransferases, demethylases, and methyllysine binders
have been identified in a large number of cancers.
These mutations may alter the catalytic activity of the methyltransferases or demethylases.
Many of these enzymes also contain chromatin-reader motifs, the mutations may also affect
the ability of these proteins to survey and bind epigenetic modifications.
 Cancer Mutations Affecting Epigenetic Regulators of Histone Phosphorylation
Recurrent mutations in signaling kinases are one of the most frequent oncogenic events
found in cancer. Some of these kinases signal directly to chromatin. Activating and
inactivating mutations of these have been noted in a range of malignancies.
Thus far, BRCA1, which contains a BRCT domain, is the only potential phosphochromatin
reader recurrently mutated in cancer. However, that BRCA1 binding to modified histones via
its BRCT domain has not yet been firmly established.
As our knowledge about histone phosphatases and phosphohistone binders increases, we are
likely to find mutations in many of these proteins that contribute to oncogenesis.
Cancer Mutations Affecting Members of the SWI/SNF Chromatin-Remodeling
Complex
The covalent modifications on the nucleosome often provides the scaffold and context for dynamic
ATP-dependent chromatin remodeling.
The mammalian chromatin-remodeling complexes
can be split into four major families:
•the switching defective/sucrose nonfermenting
(SWI/SNF) family,
•the imitation SWI (ISWI) family,
•the nucleosome remodeling and deacetylation
(NuRD)/Mi-2/chromodomain helicase DNAbinding
(CHD) family,
•the inositol requiring 80 (INO80) family.
SWI/SNF is a multisubunit complex that binds
chromatin and disrupts histone-DNA contacts.
The SWI/SNF complex alters nucleosome positioning
and structure by sliding and evicting nucleosomes to
make the DNA more accessible to transcription
factors and other chromatin regulators.
Recurrent mutations in several members of the
SWI/SNF complex have been identified in a large
number of cancers.
 Noncoding RNAs
The entire genome is transcribed; however, only 2% of this is subsequently
translated. The remaining ‘‘noncoding’’ RNAs (ncRNAs) can be roughly
categorized into small (under 200 nucleotides) and large ncRNAs.
These RNAs are increasingly recognized to be vital for normal development and
may be compromised in diseases such as cancer.
The small ncRNAs include small nucleolar RNAs (snoRNAs), PIWI-interacting
RNAs (piRNAs), small interfering RNAs (siRNAs), and microRNAs (miRNAs).
Many of these families show a high degree of sequence conservation across
species and are involved in transcriptional and posttranscriptional gene silencing
through specific base pairing with their targets.
The long ncRNAs (lncRNAs) demonstrate poor cross-species sequence
conservation, and their mechanism of action in transcriptional regulation is more
varied.
These lncRNAs appear to have a critical function at chromatin, where they may
act as molecular chaperones or scaffolds for various chromatin regulators, and their
function may be subverted in cancer.
(2) Epigenetic Reprogramming in Cancer
[Suva ML,Riggi N, Bernstein BE. Epigenetic Reprogramming in Cancer. Science 2013:339(6127):1567-1570]
 The demonstration of induced pluripotency and direct lineage conversion
has led to remarkable insights regarding the roles of transcription factors and
chromatin regulators in mediating cell state transitions.
 Beyond its considerable implications for regenerative medicine, this body
of work is highly relevant to multiple stages of oncogenesis, from the initial
cellular transformation to the hierarchical organization of established
malignancies.
 The shared mechanisms provide insights into oncogenic transformation,
tumor heterogeneity, and cancer stem cell models.
 Developmental specification is associated with global alterations in chromatin structure.
(A) In pluripotent cells, chromatin is hyperdynamic and globally accessible.
(B) Upon differentiation, inactive genomic regions may be sequestered by repressive chromatin
enriched for characteristic histone modifications and refractory to regulatory activity. These
global structures are regulated by DNA methylation, histone modifications, and numerous CRs
whose expression levels are dynamically regulated through development. In addition,
transcriptional changes are accompanied by focal alterations in chromatin structure at specific
gene loci.
Genes involved in both iPS nuclear reprogramming and cancer.
List of TFs (A) and CRs (B) implicated in iPS reprogramming together with the
malignancies in which they have established roles. These include oncogenes and
tumor suppressors directly affected by genetic alterations, as well as other genes with
mechanistic roles in cancer.
Cellular hierarchies in normal tissues and malignancies.
Normal tissues (left) and a growing list of malignancies (right) have established epigenetic
hierarchy.
Differentiation is reversible (left and right arrows). Cellular transformation (red arrow) is a
stepwise process involving accumulation of genetic and epigenetic hits.
Altered activity of key regulators, including CRs and TFs, can play dual roles in cancer,
contributing to transformation and epigenetic state transitions (oncogenic reprogramming).
The same network of regulators may act within the established tumor to rewire differentiated
cancer cells into stemlike cells, thus establishing a dynamic equilibrium between differentiation
and reprogramming.
3. Outside Influences
 Cancer is much more complex than an isolated mass of
proliferating cancer cells;
 Interactions between cancer cells and tumor microenvironment, as
well as interactions with the person as a whole, profoundly affect
cancer development;
 Tumor susceptibility.
 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 inflammatory 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.)
(Hanahan D, Weinberg RA. Hallmarks of Cancer:
The Next Generation. Cell 2011, 144:646)
 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.
(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
influenced 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.
(Hanahan D, Weinberg RA. Hallmarks of Cancer: The
Next Generation. Cell 2011, 144:646)
4. Hallmarks of cancer
肿瘤细胞十大特征：
1.自给自足生长信号（Self-Sufficiency in Growth Signals），
2.抗生长信号的不敏感（Insensitivity to Antigrowth Signals），
3.抵抗细胞死亡(Resisting Cell Death)，
4.潜力无限的复制能力(Limitless Replicative Potential)，
5.持续的血管生成(Sustained Angiogenesis)，
6.组织浸润和转移(Tissue Invasion and Metastasis)，
7.避免免疫摧毁(Avoiding Immune Destruction)，
8.促进肿瘤的炎症（Tumor Promotion Inflammation），
9.细胞能量异常（Deregulating Cellular Energetics），
10.基因组不稳定和突变（Genome Instability and Mutation）。
. (Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646)
 Self-sufficiency in growth signals
Cancer cells do not need stimulation from external signals (in the form of growth
factors) to multiply.
 Insensitivity to anti-growth signals
Cancer cells are generally resistant to growth-preventing signals from their
neighbours.
 Tissue invasion and metastasis
Cancer cells can break away from their site or organ of origin to invade
surrounding tissue and spread (metastasis) to distant body parts.
 Limitless reproductive potential
Non-cancer cells die after a certain number of divisions. Cancer cells escape this
limit and are apparently capable of indefinite growth and division (immortality).
 Sustained angiogenesis
Cancer cells appear to be able to kick start this process, ensuring that such cells
receive a continual supply of oxygen and other nutrients.
 Evading apoptosis
Apoptosis is a form of programmed cell death, the mechanism by which
cells are programmed to die after a certain number of divisions or in the event
they become damaged. Cancer cells characteristically are able to bypass this
mechanism.
 Deregulated metabolism
Most cancer cells use abnormal metabolic pathways to generate energy, a
fact appreciated since the early twentieth century with the postulation of the
Warburg hypothesis, but only now gaining renewed research interest.
 Evading the immune system
Cancer cells appear to be invisible to the body’s immune system.
 Unstable DNA
Cancer cells generally have severe chromosomal abnormalities, which
worsen as the disease progresses.
 Inflammation
Recent discoveries have highlighted the role of local chronic inflammation
in inducing many types of cancer.
思考题
1.举例说明遗传和表遗传因素在肿瘤发病中的作用。
2.什么是肿瘤的十大特征？
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