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: schsu@mail.cgu.edu.tw 電話 (03)211-8800#3690

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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.

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Textbook & Grading

Textbook: The Biology of Cancer Robert A. Weinberg Garland Sciences

Grading: Mid-term Exam: 50% Final Exam: 50%

Bonus (report): 20%

Chapter 1: The Biology and Genetics of Cells and Organisms

Charles Darwin Gregor Mendel

On the Origin of SpeciesNatural Selection

Evolution Genetics

Mendel establishes the basic rules of genetics

Genotype and PhenotypeTwo alleles

Genotype and Phenotype

Mendelian genetics helps to explain Darwinian evolution

“Junk” DNA

Biologically important sequences(~3.5% of total genome)

Human Genome Size 3 x 109 b.p.

Coding sequences Noncoding DNAPseudogenesGenes for noncoding RNAIntrons and untranslated regions of mRNARegulatory DNA sequencesRepetitive DNA sequencesMobile genetic elements (transposons) and their relics

Biologically important sequences in the human genome

Neutral mutations and evolution

Mendelian genetics governs how both genes andchromosomes behave

Mutations causing cancer occur in both the germ line and the soma

Increase and decreases in copy number of chromosomal segments

Gene expression patterns also control phenotype

Genotype embodied in DNA sequences createsphenotype through proteins

Transcription TranslationReplication

Processing of pre-mRNA

Gene expression patterns also control phenotype

Histone modification and transcription factors controlgene expression

Regulation of gene expression

Post-translationl modification of histone tails

Heritable gene expression is controlled throughadditional mechanisms

Maintenance of DNA methylation following replication

Methylation of CpG generally causes repression of nearby genes.

Unconventional RNA molecules also affect theexpression 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 cancer- brain 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 lung

uterusgallbladder

Embryonic cell layers

The first major class of nonepithelial cancers derive from the various connectivetissues, 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 formvarious components of the central and peripheral nervous systems

Some types of tumors do not fit into the major classifications

melanomasderive from melanocytes, the pigmented cells of the skin and the retina

Small-cell lung carcinomas (SCLCs) contain cells having many attributes ofneurosecretory 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 failto migrate to their proper destinations during embryonic development and persistat 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 adenomasand carcinomas

In the colon, pre-invasive growthsappear as either flat thickenings of the colonic wall (sessile polyps, not shown) or as the stalk-like growths (pedunculated polyps)

ductal carcinoma in situ (DCIS)

The lobules of the normal humanbreast

Invasive carcinomas

Classification scheme of tumors

Tumors are monoclonal growths

Monoclonality versus polyclonality of tumors

X-chromosomeinactivation patterns and themonoclonality of tumors

Additional proofs of tumor monoclonality

Cancer cells exhibit an altered energy metabolism

Warburg effect ?!

Cancers occur with vastly different frequencies indifferent human populations

Country-to-countrycomparisons of cancer incidence

The risks of cancers often seem to be increased byassignable 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)

The Ames test for gauging mutagenicity

Bruce Ames, 1975

Mutagenic versus carcinogenic potency

Mutagens may be responsible for some human cancers

51Cell (2000) 100:57

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Acquired Capability of Cancer Cells

Cell (2000) 100:57

“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

53Cell (2011) 144:646

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Emerging Hallmarks & Enabling Characteristics

Cell (2011) 144:646