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 電話 (03) #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% 3 Bonus (report): 20%

Chapter 1: The Biology and Genetics of Cells and Organisms Charles DarwinGregor Mendel On the Origin of Species Natural Selection Evolution Genetics

Mendel establishes the basic rules of genetics Genotype and Phenotype Two 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 10 9 b.p. 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 Biologically important sequences in the human genome

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

Gene expression patterns also control phenotype Genotype embodied in DNA sequences creates phenotype through proteins TranscriptionTranslationReplication

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 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 uterus gallbladder

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) ductal carcinoma in situ (DCIS) The lobules of the normal human breast

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)

The Ames test for gauging mutagenicity Bruce Ames, 1975

Mutagenic versus carcinogenic potency

Mutagens may be responsible for some human cancers

51 Cell (2000) 100:57

Acquired Capability of Cancer Cells 52 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

53 Cell (2011) 144:646

Emerging Hallmarks & Enabling Characteristics 54 Cell (2011) 144:646