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MICa 8004 - Biology of Cancer

Biology of Cancer – MICA 8004
Spring Semester, 2016
M,W,Th,F, 9:05-9:55am, 2-580 MoosTower

David Largaespada (Course Director), 6-4979,, 3-129 CCRB
Anindya Bagchi (

Martina Bazzaro (

Scott Dehm (
Timothy Hallstrom (
Ameeta Kelekar (

Carol Lange ( 

Louis Mansky (
Deepali Sachdev (
Kaylee Schwertfeger ( 

Timothy Starr (
Douglas Yee (
Katie Leehy (
Christopher Pennell (

The Biology of Cancer. 2nd Edition. Robert A. Weinberg, Garland Publishing, New York, 2013.

Course Format
The course will be divided into 15 blocks consisting of 4 meetings per block. Within each block, the first two meetings will be lectures with assigned textbook chapters and/or journal articles. These lectures will cover key concepts that you will be expected to know for the final exam. Students should expect to spend time outside of class to learn techniques relevant to the assigned reading material. Course materials will be available thru a Moodle course site.

The third meeting will be a journal club-style discussion of a paper that is related to the topic of the block. Students are expected to read the entire assigned paper before class and be ready to discuss it in detail. Students will be separated into groups and each group will be expected to present part of the paper to the class. The section your group will present will not be assigned until the day of class that you present, therefore, be prepared to discuss any part of the paper. You will have 10 minutes with your group at the beginning of class to prepare your presentation. Presentations will be approximately 5 minutes long. These assigned groups will change three times during the course. Your group assignments will be handed out the first day of class.

The instructor will e-mail a problem-solving quiz to each student shortly after the third meeting. Students will e-mail their answers back to the instructor before the beginning of the fourth meeting, after which the instructor will present acceptable answers and lead a discussion of alternative answers and their weaknesses. The instructor will also summarize the Key Concepts of the block at the fourth meeting.

The exams will include 15 problem-solving quizzes, one per block, and a fact-based short answer format final exam. The quiz may be one essay question or multiple questions. The quizzes will be e-mailed as MS Word documents by the block instructor to the students shortly after the third meeting of each block. The completed quizzes must be e-mailed by the students back to the block instructor by the beginning of the fourth meeting. Answers must be limited to 1 page, 12pt Times New Roman font, 1-inch margins, single spacing. Answers longer than 1 page will be given a score of 0. Any material available in the scientific literature may be used to answer the questions. However, students are expected to answer their own quiz independently. None of the quiz questions may be discussed with other members of the class until after the quiz. According to criteria discussed during the fourth session, the instructor will grade each quiz, and the graded quiz will be returned to students via e-mail.

The final exam will be 1 hour in length, closed book, short answer format, and focused on the Key Concepts from each block.

Course Points
Exams - 10 points will be given for each take home quiz for a total of 150 points and 75 points will be given for the final exam.

Attendance - 5 points will be given for participation during each block for a total of 75 points. Attendance points will be based on attending all classes in each block. Attendance of all meetings is expected, with an exception for one excused absence during the course (NOT one excused absence per block). Excused absences MUST be for legitimate reasons and are to be requested from the course director, David Largaespada, when possible, before the missed meeting or immediately following.

Take Home Quizzes (15 at 10 pts each) – 150 points
Attendance Points (15 at 5 pts each block) – 75 points
Final Exam – 75 points
Total Points Available – 300

Block Topic Lecturer Group Dates (W,Th,F.M)
1 Introduction to the Course/Cancer Pathology/The TCGA Starr A Groups Jan. 20, 21, 22, 25
2 Cancer Genetics: Cancer Viruses and Experimental Genetics Mansky A Groups Jan. 27, 28, 29,  Feb. 1
3 Cell Signaling I: The cytoplasm (GF receptors, G-protein coupled receptors) Leehy A Groups Feb. 3, 4, 5, 8
4 Cell Signaling II: RAS, SRC, P13K, SHH, WNT, TGF Lange A Groups Feb. 10, 11, 12, 15
5 Cell Signaling III:  The nucleus (steroid hormone receptors, Fos/Jun, JAK-STAT) beta Dehm A Groups Feb. 17, 18, 19, 22
6 Tumor suppressor genes; Genome Instability Bagchi B Groups Feb. 24, 25, 26, 29
7 RB/Cell Cycle P53 Hallstrom B Groups March 2, 3, 4, 7
8/9 Apoptosis Autophagy/Metabolism Kelekar B Groups March 9, 10, 11, 21, 23, 24, 25, 28
10 Invasion & Metastasis Schwertfeger B Groups March 30, 31, April 1, 4
11 Angiogenesis Bazzaro C Groups April 6, 7, 8, 11
12 Cellular Immortalization; Cancer Stem Cells Largaespada C Groups April 13, 14, 15, 18
13 Cancer Therapy I: Tumor Immunology & Immune Therapies Small molecules and Targeted Therapy Pennell C Groups April 20, 21, 22, 25
14 Human Cancer and Microbes: Bacteria and Viruses Largaespada C Groups April 27, 28, 29, May 2
15 Cancer Therapy II: Small molecules and Target Sachdev/Yee C Groups May 4, 5, 6


Spring break March 14th -18th

MICA 8004 Reading List - Spring Semester 2016

Please read the material listed for each date BEFORE coming to class.

Block 1: Cancer Pathology

Jan. 20th – 1) Skim the first chapter of the textbook (Weinberg Chapter 1, pgs. 1-29). Use the bold words throughout the chapter to judge whether or not you already have this knowledge. If you can read the bold words and could define them in an essay question on a test, then you don’t need to read the chapter thoroughly. Watch at least one of the movies on the CD that comes with the books. This chapter is a rewview of the fundamentals of genetics. You should already know most of what is in this chapter.

2) Go to The Cancer Genome Atlas homepage ( Attempt to download all the somatic mutations that have been found in the colon adenocarcinoma samples analyzed by the TCGA. Hint: Use the data matrix. The downloaded file will be a zip file ~50 Mb (i.e. I wouldn’t try this at home if you have a slow connection). Once you unzip the file, see if you can find the first mutation listed. Hing: the file will have the extension .maf and you should open it using a basic text editor.

Jan. 21st - 1) Start by reading the Synopsis and prospects and Key concepts (pp. 66-69) in Weinberg, Chapter 2. If some of the key concepts are new to you, read that portion of the chapter. Spend some time on the first part of the chapter learning nomenclature used to describe cancer pathology.

2) Read Hanahan, D. and Weinberg, R.A. Hallmarks of Cancer: The Next Generation. 2011. Cell 144, 646-674.

Jan. 22nd - Journal article: Be prepared to present Figures 1 thru 4 and extended Figure 7. Whole genome characterization of chemoresistant ovarian cancer. Patch, et al., Nature, 2015 May 28: 521(7553):488-94.
Take home exam will be distributed at the end of the class.

Jan. 25th – (additional readings, not required)

A good historical account of cancer research: "The Emperor of All Maladies: A Biography of Cancer" by Siddhartha Mukherjee. This is a 1,000 page epic, but it is good for skimming.

Block 2: Cancer Genetics: Cancer Viruses and Experimental Genetics

Jan. 27th - Weinberg Chapter 3, read the Synopsis, Prospects, & Key Concepts pp. 86-90. Skim the chapter and read the bolded words/terms. If you understand key concepts and bolded word/terms, no further reading required.

Temin HM and H Rubin. 1958. Characteristics of an assay for Rous sarcoma virus and Rous sarcoma cells in tissue culture. Virology 6:669-688.

Jan. 28th - Weinberg Chapter 4, read the Synopsis, Prospects, & Key Concepts pp. 112-116. Skim the chapter and read the bolded words/terms. If you understand key concepts and bolded word/terms, no further reading required.

Jan. 29th - Stehelin D, HE Varmus, JM Bishop, PK Vogt. 1976. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260:170-173.

Feb. 1st – (additional readings, not required)

Read "The Emperor of All Maladies: A Biography of Cancer" by Siddhartha Mukherjee.

Block 3: Cell Signaling I: The Cytoplasm (GF Receptors, G-Protein Coupled Receptors)

*Please use the textbook as a general point of reference for background to signaling. Topics of interest include mechanisms of growth factor tyrosine kinase receptor (EGFR family members) signaling and regulation of downstream protein kinase cascades (MAPKs and PI3K/Akt). The context for this section is the role of dysregulation of these regulatory molecules in cancer biology.

Feb 3rd – Weinberg Chapter 5* – Growth Factors, Kinases and Tyrosine Kinase Receptors

Feb 4th – Weinberg Chapter 5 cont.* – Tyrosine Kinase Receptors, Other Receptors and Ras

Yarden, Y. and G. Pines. The ERBB network: at last, cancer therapy meets systems biology. 2012. Nature Reviews. 12:553-563.

Feb 5th - E.M. Tricker, C. Xu, S. Uddin, M. Capelletti, D. Ercan, A. Ogino, C.A. Pratilas, N.Rosen, N.S. Gray, K.K. Wong, P.A. Janne. (2015) Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer. Cancer Discovery. 5:960–971.

Feb 8th – Review / Discussion of Key Concepts

Block 4: Cell Signaling II: RAS, SRC, P13K, SHH, WNT, TGFbeta

Feb. 10th - Weinberg Chapter 6, pgs. 175-202

Feb. 11th - Weinberg Chapter 6, pgs. 206-228

Feb. 12th - Yan Wang,Qingqing Ding,Chia-Jui Yen, et. al. The Crosstalk of mTOR/S6K1 and Hedgehog Pathways. Cancer Cell, Volume 21, Issue 3, 374-387, 20 March 2012

Feb. 15th – (additional readings, not required)

Cancer Cell. 2012 Nov 13;22(5):571-84. doi: 10.1016/j.ccr.2012.08.013. Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation. Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Céspedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, Byrom D, Riera A, Rossell D,Mangues R, Massagué J, Sancho E, Batlle E.

Cancer Cell. 2012 Nov 13;22(5):668-82. doi: 10.1016/j.ccr.2012.10.009. Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E Melanomas. Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E, Zubrowski M, Huang A, Wong WL, Callahan MK, Merghoub T, Wolchok JD, de Stanchina E,Chandarlapaty S, Poulikakos PI, Fagin JA, Rosen N.

Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC, Gao S, Mills GB,Brugge JS. Cancer Cell. 2012 Feb 14;21(2):227-39.

Block 5: Cell Signaling III: The Nucleus (Steroid Hormone Receptors, Fos/Jun, JAK-STAT)

Feb. 17th - Weinberg Chapter 1.6, 1.7, 1.8, and Weinberg Chapter 6.1, 6.5, 6.6, 6.8, 6.10, 6.12 (these should already have been read in preparation for previous Blocks)

Dawson MA and Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 150: 12-27, 2012.

Feb. 18th - Jozwik KM, Carroll JS. Pioneer factors in hormone-dependent cancers. Nature Reviews Cancer. 12:381-385, 2012.

Feb. 19th - Lovén J et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 153: 320, 2013.

Feb. 22nd – (additional readings, not required)

Kim TK and Shiekhattar R. Architectural and Functional Commonalities between Enhancers and Promoters. Cell. 162: 948-59, 2015.

Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 54: 728-36, 2014.

Rathert P et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525: 543-7, 2015.
ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57-74, 2012.

Block 6: Tumor Suppressor Genes, Genome Instability

Feb. 24th - Weinberg Chapter 7, pgs. 209-254

Feb. 25th - Weinberg Chapter 12, pgs. 463-526

Feb. 26th - The Landscape of Microsatellite Instability in Colorectal and Endometrial Cancer Genomes Cell, Volume 155, Issue 4, 7 November 2013, Pages 858–868

Feb. 29th – (additional readings, not required)

Block 7: RB/Cell Cycle/P53

March 2nd - Weinberg Chapter 8

March 3rd - Weinberg Chapter 9.1-9.12

March 4th – Inhibition of Pluripotency Networks by the Rb Tumor Suppressor Restricts Reprogramming and Tumorigenesis. Cell Stem Cell. 2015 Jan 8;16(1):39-50.

March 7th – (additional readings, not required)

Keith W. Orford1 & David T. Scadden. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nature Reviews Genetics 9, 115-128 (February 2008) | doi:10.1038/nrg2269

Kastan M., Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004. Nov 18; 432(7015):316-23.

Block 8/9: Apoptosis Autophagy/Metabolism

March 9th - Ola, M.S., M. Nawaz, and H. Ahsan, Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem, 2011. 351(1-2): p. 41-58

Additional Reading (optional) - Youle, R.J. and A. Strasser, The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol, 2008. 9(1): p. 47-59

March 10th - Mizushima, N. and M. Komatsu, Autophagy: renovation of cells and tissues. Cell, 2011. 147(4): p. 728-741

March 11th – Review Apoptosis and Autophagy

March 21st – Cantor, J.R. and D.M. Sabatini, Cancer cell metabolism: one hallmark, many faces. Cancer Discov, 2012. 2(10): p. 881-898

Additional Reading (optional) - Leone, R.D. and R.K. Amaravadi, Autophagy: a targetable linchpin of cancer cell metabolism. Trends Endocrinol Metab, 2013. 24(4): p. 209-217.

March 23rd – Review Cancer Metabolism

March 24th - Xie, J.M., et al. (2014). TIGAR has a dual role in cancer cell survival through regulating apoptosis and autophagy. Cancer Res 74, 5127-5138.

March 25th - Back-to-back papers on mitochondrial myruvate transporter:
1. Yang, C., , et al. (2014). Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell 56, 414-424.
2. Schell, J.C., et al. (2014). A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell 56, 400-413.

Additional Reading (optional) - Szlosarek, P.W., Lee, S., and Pollard, P.J. (2014). Rewiring mitochondrial pyruvate metabolism: switching off the light in cancer cells? Mol Cell 56, 343- 344.

Vacanti, N.M., et al. (2014). Regulation of substrate utilization by the mitochondrial pyruvate carrier. Mol Cell 56, 425-435.

March 28th – Discussion and review of assignments

Block 10: Invasion and Metastasis

March 30th - Weinberg Chapter 14 pgs. 641-685

March 31st - Weinberg Chapter 14 pgs. 686-689, 695-719

April 1st - A Noncanonical Frizzled2 Pathway Regulates Epithelial-Mesenchymal Transition and Metastasis. Gujral et al., Cell 159(4), 844-856, 2014.

April 4th – (additional readings, not required)
1. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors
and cancer: trials and tribulations. Science 2002;295(5564):2387-92.

2. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev
Cancer 2009;9(4):239-52.

3.Klein CA. Cancer. The metastasis cascade. Science 2008;321(5897):1785-7.

4.Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial- mesenchymal transition generates cells with properties of stem cells. Cell 2008;133(4):704-15

Block 11: Angiogenesis

April 6th - Weinberg Chapter 13:1-13:6

April 7th – Weinberg Chapter 13:7-13:11

April 8th - Rac1/Pak1/p38/MMP-2 axis regulates angiogenesis in ovarian cancer. Gonzalez-Villasana, Fuentes-Mattei, Ivan, Dalton, Rodriguez-Aguayo, Fernandez-de Thomas, Aslan, Monroig-Bosque, Velazquez-Torres, Previs, Pradeep, Kahraman, Wang, Kanlikilicer, Ozpolat, Calin, Sood, Lopez-Berestein. Clin Cancer Res. 2015 Jan 16. pii: clincanres.2279.2014. [Epub ahead of print]

April 11th – (additional readings, not required)

Block 12: Cellular Immortalization; Cancer Stem Cells

April 13th - Weinberg Chapter 10, pgs. 357-398

April 14th - Weinberg Chapter 11, pgs. 399-441

April 15th – Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Batista LF, et al. Nature. 2011 May 22; 474(7351):399-402. doi: 10.1038/nature10084.

April 18th – (additional readings, not required)
Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Tomasetti C, Vogelstein B. Science. 2015 Jan 2;347(6217):78-81. doi: 10.1126/science.1260825.

Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R, Kemler R. Science. 2012 Jun 22;336(6088):1549-54. doi: 10.1126/science.1218370.

Block 13: Cancer Therapy I: Tumor Immunology and Immune Therapies

April 20th - Weinberg Chapter 15

April 21st - Weinberg Chapter 15

April 22nd – Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015 Sep 2;7(303):303ra139.

April 25th – (additional readings, not required)
Barrett DM, Grupp SA, June CH. Chimeric Antigen Receptor-and TCR-Modified T Cells Enter Main Street and Wall Street. J Immunol. 2015 Aug 1;195(3):755-61.

Block 14: Human Cancer and Microbes: Bacteria and Viruses

April 27th - Weinberg Chapter 11, pgs. 488-500

April 28th - Schwabe RF and Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013 Nov;13(11):800-12. doi: 10.1038/nrc3610. Epub 2013 Oct 17.

April 29th - Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008 Feb 22;319(5866):1096-100. doi: 10.1126/science.1152586. Epub 2008 Jan 17.

May 2nd – (additional readings, not required)
Urisman et al., Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant. PLoS Pathogens. 2006 Mar;2(3):e25. Epub 2006 Mar 31.

Block 15: Cancer Therapy II: Small Molecules and Targeted Therapy

May 4th – Weinberg Chapter 16 pgs. 797-815

May 5th - Weinberg Chapter 16 pgs. 815-818; 825-833; 844-860

May 6th - TBD

Final Exam

May 12th – 1:30-3:30pm, Location TBD

MICA 8004 – Biology of Cancer
Key Concepts

Block 1: Cancer Pathology and the TCGA
1. Use and understand terminology describing pathological and molecular processes in cancer development and progression
2. Enumerate and provide an overview of the hallmarks of cancer and their significance to diagnosis and therapy
3. Discuss changes in the dynamics of cancer incidence and prevalence in the past 3-5 decades (i.e., answer the question, “is there a cancer epidemic?”)
4. Describe the histological origins of cancer and their relationship to processes of developmental biology

Block 2: Cancer Genetics: Cancer Viruses, Experimental Genetics
1. Know how Rous sarcoma virus helped to confirm that viruses could cause cancer
2. Know the basic properties of transformed cells
3. Describe the basic genetic approaches to engineering mice for the study of tumogenicity
4. Describe the histological origins of cancer and their relationship to processes of developmental biology
5. Know the basic properties of retrovirus structure and replication
6. Describe how Rous sarcoma virus and acutely transforming retroviruses cause cancer
7. Know how slowly transforming retroviruses cause cancer and how to identify cancer causing insertions in chromosomal DNA
8. Describe how DNA viruses, e.g., SV40, cause cancer

Block 3: Cell Signaling I: The Cytoplasm (GF Receptors, G-Protein Coupled Receptors)
1. How growth factors and growth factor receptors facilitate cell-to-cell communications.
2. The mechanism of kinases and their importance for signal transduction.
3. The structure and function of receptor tyrosine kinases.
4. Basics of other receptors in cell-to-cell signaling.
5. How the above (1-4) can be altered in the context of cancer and what that means for the development of cancer therapy.

Block 4: Cell Signaling II: RAS, SRC, P13K, SHH, WNT, TGFbeta
1. Regulation of small GTPases by GEFs and GAPs
2. Assembly of signaling complexes involving SH2 and SH3 domain containing proteins
3. PI3K signaling as a master regulator of cancer development and maintenance
4. Signal pathway regulation by a destruction complex
5. The paradoxical role of TGF-beta in cancer development and progression
6. Feedback signal pathway regulation in cancer cell signaling

Block 5: Cell Signaling III: The Nucleus (Steroid Hormone Receptors, Fos/Jun, JAK-STAT)
1. Transcription and deregulation in cancer
2. Myc, Fos/Jun, STATs and oncogenic signal transduction pathways
3. Hormone receptors and the development and progression of prostate and breast cancers.
4. Androgen and estrogen signaling pathways, “molecularly targeted therapies” and resistance
5. Therapeutic targeting of epigenetic deregulation in cancer

Block 6: Tumor Suppressor Genes: Genome Instability
1. Mechanisms for loss of heterozygoisity (LOH) during tumorigenesis
2. DNA repair mechanisms are tumor suppressive
3. Base excision repair
4. Mismatch repair
5. Homologous recombination

Block 7: RB/Cell Cycle/P53
1. The cell cycle, cyclins and their catalytic CDK binding partners
2. Timing and signals of cell fate, such as growth, quiescence, apoptosis, differentiation or senescence
3. E2F transcription factors associated with promoters of genes that control cell cycle, DNA replication and mitosis.
4. Hypophosphorylated pRb and hyperphosphorylated pRb
5. Loss of pRb function
6. Inactive pRb and activation of pro-apoptotic or senescence programs.

Block 8/9: Apoptosis /Autophagy/Metabolism
1. Programmed Cell Death and Apoptotic pathways in normal cells and their aberrant regulation in cancer, with special emphasis on the involvement of the Bcl-2 family of proteins
2. Autophagy as a Stress Response in normal cells, and the contradictory and contextual roles for deregulated Autophagy in tumor suppression and tumor progression
3. The Warburg Hypothesis and Metabolic Reprogramming in actively proliferating normal cells and cancer cells
4. Apoptosis, Autophagy and Metabolism are closely linked – understanding the crosstalk, the overlap and the shared regulators

Block 10: Invasion and Metastasis
1. Metastatic cascade steps including 1) local invasion, 2) intravastion, 3) transport, 4) extravasation, 5) formation of micrometastases and 6) colonization
2. The process of epithelial-mesenchymal transition (EMT), during which epithelial gene expression is lost and mesenchymal gene expression is gained, contributes to tumor cell motility and invasiveness
3. MMPs promote invasion by degrading the basement membrane and releasing growth and angiogenic factors from the extracellular matrix.
4. Metastasis involves changes in the tumor cells and contributions from stromal/host cells both within the local microenvironment and at distant sites

Block 11: Angiogenesis
1. Tumors and intercommunication between various cell types
2. The recruitment of macrophages, fibroblasts and fibroblast and their key roles during tumor-associated angiogenesis
3. The “Angiogenic switch” and tumor-associated angiogenesis as a critical determinant of tumor growth.
4. Neo-angiogenesis as target for development of novel anticancer agents as angiogenesis inhibitors are designed to “cut off cancer’s supplies”

Block 12: Cellular Immortalization; Cancer Stem Cells
1. Cancer cells acquire and display distinct neoplastic traits (e.g. via activation of oncogenes and loss of tumor suppressor genes) that usually require several decades’ time to develop
2. A long succession of growth-and-division cycles occur as they evolve toward the neoplastic growth state
3. Incipient cancer cells must breach the barrier that normally limits their proliferative potential (and thus become immortal so that they can successfully complete the multiple steps of tumor development
4. Normal cells evolve into cells with increasingly neoplastic phenotypes through a process termed tumor progression
5. This is driven by a sequence of randomly occurring mutations and epigenetic alterations of DNA that affect the genes controlling
• Cell proliferation
• Survival
• Other traits associated with the malignant cell phenotype
6. A subset of cells within a tumor mass actually are required for long term propagation of the tumor, are targets for mutations that cause tumor progression, and may be the source of metastatic disease and recurrent disease after treatment

Block 13: Cancer Therapy I: Tumor Immunology and Immune Therapies
1. Immune surveillance constantly eliminates nascent tumors and, by definition, cancer has escaped immune surveillance.
2. The characteristics of the immune system that make it attractive for cancer therapy include specificity, potency, and memory.
3. Immune therapeutics for cancer include monoclonal antibodies, adoptively transferred cells, and vaccines.
4. Overcoming cancer-mediated immune suppression is critical for the success of cell-based immune therapies.

Block 14: Human Cancer and Microbes: Bacteria and Viruses
1. Viruses and bacteria can cause human cancer. Roughly 20% of human cancer has a viral etiology.
2. Roughly 20% of human cancer cases have a viral etiology.
3. Microbes are incomplete carcinogens, often cause chronic inflammation leading to cancer.
4. Viral proteins designed to enhance replication can contribute to cancer development.
5. Criteria for establishing causation differs from Koch’s postulates

Block 15: Cancer Therapy II: Small Molecules and Targeted Therapy
1. Understand the role of systemic therapy in reducing breast cancer deaths.
2. Identifying prognostic factors and their roles as targets for cancer therapy.
3. Describe the role for targeted therapies and mechanism of action.
4. Resistance to targeted therapies is frequently seen and can be either de novo or acquired. Understand that targeting multiple pathways may be critical