Download 0922 Cancer Biology

LS4120/BMM451
腫瘤生物學及癌症治療
Cancer Biology & Cancer Therapy
許勝傑 博士
長庚大學生物醫學系 助理教授
生物醫學研究所 生化暨細胞分子生物學組
E-mail: [email protected]
電話 (03)211-8800#3690
Course Description


本課程旨在講授與腫瘤發生與惡化相關的細胞與分子機制，包括腫瘤細胞
的特性、致癌基因與抑癌基因與致癌病毒的作用、腫瘤細胞的生長與死亡、
腫瘤的侵犯與轉移。此外本課程也將介紹目前癌症治療的理論基礎以及目
前癌症藥物研發之趨勢，希望透過本課程的介紹讓學生對於腫瘤發生與惡
化的機制有所了解，也做為未來研究生物醫學與腫瘤治療的基礎。
This advanced course aims to familiarize the students with current
understanding in the field of cancer biology and cancer therapy. The
course will emphasize on the molecular mechanisms underlying major
cancer-associated phenotypes and cancer treatment. Topics will include
an introduction to cancer burden, proliferative signaling, growth control,
angiogenesis, metastasis, tumor microenvironment and immune
suppression. The course will also cover recent advance in cancer
genetics and cancer genomics. The class should be of interest to
undergraduate students in biomedical science who may wish to
consider a career in cancer research.
2
Textbook & Grading
Textbook:
 The Biology of Cancer
 Robert A. Weinberg
 Garland Sciences
Grading:
 Mid-term Exam: 50%
 Final Exam: 50%
Bonus (report): 20%
3
Chapter 1:
The Biology and Genetics of Cells and Organisms
Charles Darwin
Gregor Mendel
On the Origin of Species
Natural Selection
Evolution
Genetics
Mendel establishes the basic rules of genetics
Two alleles
Genotype and Phenotype
Mendelian genetics helps to explain Darwinian evolution
Genotype and Phenotype
Biologically important sequences in the human genome
Human Genome Size 3 x 109 b.p.
Biologically important sequences
(~3.5% of total genome)
“Junk” DNA
Coding sequences
Noncoding DNA
Pseudogenes
Genes for noncoding RNA
Introns and untranslated regions of mRNA
Regulatory DNA sequences
Repetitive DNA sequences
Mobile genetic elements (transposons) and their relics
Neutral mutations and evolution
Mendelian genetics governs how both genes and
chromosomes behave
Mutations causing cancer occur in both the germ
line and the soma
Increase and decreases in copy number of
chromosomal segments
Genotype embodied in DNA sequences creates
phenotype through proteins
Gene expression patterns also control phenotype
Replication
Transcription
Translation
Processing of pre-mRNA
Gene expression patterns also control phenotype
Histone modification and transcription factors control
gene expression
Regulation of gene expression
Post-translationl modification of histone tails
Heritable gene expression is controlled through
additional mechanisms
Maintenance of DNA methylation following replication
Methylation of CpG generally causes repression of nearby genes.
Unconventional RNA molecules also affect the
expression of genes
MicroRNA and gene regulation.
Chapter 2: The Nature of Cancer
Tumors arise from normal tissues
Metastasis of cancer cells to distant sites.
Melanolma
lung
metastases
Colon cancer
liver
metastases
Breast cancerbrain
metastases
Tumors arise from many specialized cell types
throughout the body
The majority of human tumors arise from epithelial tissues. 80%
Architecture of epithelial tissues
kidney
gallbladder
lung
uterus
Embryonic cell layers
The first major class of nonepithelial cancers derive from the various connective
tissues, all of which share a common origin in the mesoderm of the embryo.
The second group of nonepithelial cancers arise from the various cell types that
constitute the blood-forming (hematopoietic) tissues
The third and last major grouping of nonepithelial tumors arises from cells that form
various components of the central and peripheral nervous systems
Some types of tumors do not fit into the major classifications
melanomas
derive from melanocytes, the pigmented cells of the skin and the retina
Small-cell lung carcinomas (SCLCs) contain cells having many attributes of
neurosecretory cells, such as those of neural crest origin in the adrenal glands
that sit above the kidneys.
Teratomas seem to arise from germ cell (egg and sperm) precursors that fail
to migrate to their proper destinations during embryonic development and persist
at ectopic (inappropriate) sites in the developing fetus.
Cancers seem to develop progressively
Normal versus hyperplastic epithelium
Metaplastic conversion of epithelia
Barrett’s esophagus, in which the normally present squamous epithelium is
replaced by secretory epithelial cells of a type usually found within the
stomach
Formation of dysplastic epithelium
The cytological changes include variability in nuclear size and shape,
increased nuclear staining by dyes, increased ratio of nuclear versus
cytoplasmic size, increased mitotic activity, and lack of the cytoplasmic
features associated with the normal differentiated cells of the tissue.
Pre-invasive adenomas
and carcinomas
In the colon, pre-invasive growths
appear as either flat thickenings of
the colonic wall (sessile polyps, not
shown) or as the stalk-like growths
(pedunculated polyps)
The lobules of the normal human
breast
ductal carcinoma in situ (DCIS)
Invasive carcinomas
Classification scheme of tumors
Tumors are monoclonal growths
Monoclonality versus polyclonality of tumors
X-chromosome
inactivation patterns
and the
monoclonality of
tumors
Additional proofs of tumor monoclonality
Cancer cells exhibit an altered energy metabolism
Warburg effect ?!
Cancers occur with vastly different frequencies in
different human populations
Country-to-country
comparisons of cancer incidence
The risks of cancers often seem to be increased by
assignable influences including lifestyle
Specific chemical agents can induce cancer
The first induction of tumors by chemical carcinogens
In 1915, Katsusaburo
Yamagiwa reported the first
successful induction of
cancer by repeated
treatment of rabbit ears with
a chemical carcinogen, in
this case coal tars (柏油).
Structures of carcinogenic hydrocarbons
Both physical and chemical carcinogens act as mutagens
(X-ray)
(alkylating agents)
Bruce Ames, 1975
The Ames test for gauging mutagenicity
Mutagenic versus carcinogenic potency
Mutagens may be responsible for some human cancers
51
Cell (2000) 100:57
Acquired Capability of Cancer Cells
“We suggest that most if not all
cancers have acquired the same set
of functional capacities during their
development, albeit through
various mechanistic strategies.”
Hanahan & Weinberg
52
Cell (2000) 100:57
53
Cell (2011) 144:646
Emerging Hallmarks & Enabling Characteristics
Cell (2011) 144:646
54