Cancer Cell Heterogeneity & Heterotypic Interactions in Tumors Folder Title: Hetero(NoTP) Updated: February 26, 2018 See Chapter 13 in Weinberg’s Biology of Cancer, Edition 2: pp. 577to 640, Heterotypic Interactions Folder Title: Hetero One important biological characteristic of clinical cancers is that they are comprised of different cell populations even though the cancer itself is often derived from a single neoplastic precursor cell. This feature of cancer cell diversity makes it difficult to define the biology of "the cancer cell", and it makes it difficult to manage the developing neoplastic condition.

Second 3rd of Biology of Cancer: How Do Cancers Get that Way? What are cancer cells like? (Cell Properties; Immortalization) Chapter 2 (Parts); Chapter 10 , pp 391 - 437 How do cancer cells interact with each other and with normal supportive tissue? (Heterogeneity) Chapter 13: Heterotypic Interactions. pp 577 – 640) How do cancers develop and change? (Progression) Chapter 11: Multi-step Tumorigenesis. pp 439 - 510 How do cancer cells and cancerous neoplasms grow? (Growth) Chapter 5: Growth Factors and Receptors, pp 131 - 174 How do cancer cells become invasive and become able to spread? (Invasion and Metastasis) Chapter 14: Moving Out: Invasion and Metastasis, pp 641 - 722 What do we study in order to understand metastatic cancers? (Met Models) Chapter 14

Selected Molecular and Phenotypic Characteristics of Cancer Cells: Cancer Cells Are, Have, Can, or Show: Embryonic, Undifferentiated Large Nucleus, Excess DNA Defects in DNA Repair Secrete Proteases for Invasion Aberrant Mitoses Rapid Cell Division Anchorage-independent growth and cytoskeletal anomalies Failure to senesce (failure to exhibit ageing) Failure to invoke Apoptosis Invasive Metastatic Induce host cell support

Selected Molecular and Phenotypic Characteristics of Cancer Cells: Ideas for Therapy Cancer Cells Are, Have, Can, For Therapy we Can: or Show: Embryonic, Undifferentiated Induce differentiation Large Nucleus, Excess DNA DNA-directed Anticancer Agents & XRay Defects in DNA Repair DNA-directed Anticancer Agents & Xray Secrete Proteases for Invasion Protease Inhibitors Aberrant Mitoses Mitotic Poisons Rapid Cell Division Anti-proliferative agents Anchorage-independent growth Cytoskeletal-directed agents: Microtubule and cytoskeletal anomalies and microfilament-directed Failure to senesce (to exhibit ageing) Inhibit telomerase Failure to invoke Apoptosis Activate Cell-death programs Invasive Inhibit proteolytic activity, inflammatory activity and motility Metastatic Inhibit seeding at distant sites Induces host cell support Inhibit angiogenesis and other host responses supporting tumor growth

What If Different Cancer Cells within the Cancer in a single patient respond differently from one another? Science, February 1, 2013; Volume 339, pages 528-529 “Cancer Cell Phenotypes, in Fifty Shades of Grey” Science Perspective in Cancer Distinct Clonal Populations within a single tumor respond to signals and to chemotherapy differently from one another leading to differential clonal evolution and clonal survival . These differences are not based solely on genetic heterogeneity. Epigenetic differences and tumor micro-environment affect clonal heterogeneity.

What If Different Cancer Cells within the Cancer in a single patient respond differently from one another? Science, February 1, 2013; Volume 339, pages 528-529 “Cancer Cell Phenotypes, in Fifty Shades of Grey” Science Perspective in Cancer Clones with high proliferative capacity take over tumor during growth. “Pink” cells with low proliferative capacity survive treatment with DNA-directed anti-cancer agents.

Differences Among Cancer Cells and Tumors in Different Patients Different Organ Site and Cell of Origin Differences based on Sex, Age, Hormonal Status Differences Based on Genetic Variations Among Hosts Differences in Host Response

Differences Within a Tumor in a Single Patient Progressive Overall Changes During Tumor Development Temporal Changes Involving Cycling and Non-Cycling Cells Differences Based on Host Cell and Tissue Infiltration and Cancer Cell – Host Cell Interaction (Heterotypic Interactions)

This will come up as printed News Note from Science With respect to: Differences in Cancer Clones Based on Cancer Cell Interactions with Host Cells and on Tissue Infiltration: Respect Thy Neighbor: Stromal Cell Interactions in Cancer (Principles only. No intent to memorize signaling pathways) This will come up as printed News Note from Science http://tpfondy.syr.edu/bio501/501Persons/scans/Stromal&Cx.pdf

Importance of Heterogeneity Interaction of Sub-Populations in Growth Control Generation of Metastatic Sub-Populations Differences in Chemotherapeutic Susceptibility Generation of Drug Resistant Sub-Populations Immunological Variations

Extent of Heterogeneity Found in Experimental and Spontaneous Animal Tumors In Long-Passaged Lines In Tumors of Recent Origin Found in Clinical Human Cancers Tumors of Every Major Histological Type Found in Chemically, Virally, and Radiation-induced Tumors

Properties That Are Heterogeneous Morphology Histology Karyotype Growth Rate Cell Products Receptors Enzymes Immunology Invasive & Metastatic Properties Signaling Pathway Anomalies Pathobiology in Patients

Possible Sources of Tumor Cell Heterogeneity Heterogeneity of tumor cells originally transformed Differences in Inter-cellular Environments During transformation During progression Inherent Genetic Instability and Selection of Variants Cellular Anaplasia and Aberrant Cell Function In Vivo Host-Based Effects Fusion of Different Cells Neoplastic and Normal Host Cell fusion Fusion of neoplastic cells Cell Selection during Drug Treatment

Example of Heterogeneity among Cancer Cells in a Single Patient Pleural effusion, non-small cell lung carcinoma in a patient. Heterogeneity in chromosome number and in nuclear size Chromosome 11 is Blue-Green. Chromosome 17 is pink by FISH with DNA Probes Figure 11.19 The Biology of Cancer (© Garland Science 2007) p. 422

Two Turning Point Questions Please clear desktop No communication verbal or electronic

Reductionism in Science and Medicine Heterotypic Interactions Among Cancer Cells and Host Supporting Cells and Tissues Reductionism in Science and Medicine Think Football!!!

What Determines the Outcome of a Football Game? The “Cells” The Players on “your team” How well they work together (Offense and Defense) The Supporting Tissues 3. The coaching staff 4. The play book and play selection 5. Clock management 6. Effectiveness of Practices 7. The other team and their steps 1 to 14 8. The referees 9. The replay booth 10. The weather 11. Last week’s game 12. The crowd 13. Dumb Luck 14. Who inflated the football.

Different Growth Conditions for Human Tumor Arising in a Patient (Column 2) vs Human Tumor Grown in Culture Under Conditions that Mimic In Vivo Growth (Column 3) Vs Human Cancer Cells Grown in Culture in Flat Culture in Flat Culture Flasks (Column 4) Pa = Pascals, indicating pressure from mechanical stiffness

In original Patient In Nude Mice In Cell Culture

Infiltrating Host Stromal Cells (Blue) Ductal Carcinoma of the Breast (Brown Membranes with Blue Nuclei) Infiltrating Host Stromal Cells (Blue)

TAS = Tumor Associated Stroma Normal Colon Mucosa Colon Carcinoma

Normal Stromal Stomach Tissue Adenocarcinoma of Stomach

Human Hodgkins Lymphoma Normal Lympho-cytes Neoplastic Reed-Sternberg Cell (Note “Owl Eyes”)

Cell Types in the Stroma of Various Human Carcinomas

Prostate Tumors from Mice that have genetically altered stromal Fibroblasts Heterotypic Interaction between Epithelial Cells and Stromal Fibroblasts Supports Prostatic Carcinoma Carcinoma Hi Mag Carcinoma Inactivation of TGF-Beta Growth Factor Receptor in stromal fibroblasts produces epithelial cells and stromal cells that are hyperplastic. Stromal cells produced Hepatocyte growth factor (HGF) that prevents inhibition of epithelial cell proliferation by TGFB. Normal mouse prostatic tissue with normal TGF-Beta Type II Growth Factor Receptor TGF = Transformation Growth Factor

Growing Robustly Cell debris and dead cells Excised Basal Cell Carcinoma. Reimplanted into original patient at a distant site, without or with associated stromal tissue. Excised the implanted tumors at 5 weeks. Cell debris and dead cells Growing Robustly

Colon Carcinoma Metastatic to the Liver Metastatic colon carcinoma (Blue) has ductal morphology of the original primary tumor (Black arrows)

Possible Therapies Based on Cancer Cell Supportive Cell (Stromal) Interactions

One Turning Point Question Please clear desktop No communication verbal or electronic

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The Story of the Africa Mercy Stories of People, Tumors, Blindness, and Childhood Death The Story of the Africa Mercy 60 Minutes, February 17, 2013 Africa Mercy: Hospital of hope - 60 Minutes - CBS News ►► www.cbsnews.com/video/watch/?id=50141230n 12 Minute Video https://www.youtube.com/watch?v=TfjYeQzCwzU Copy this youtube link to your browser

End of Heterogeneity Presentation: Tuesday, March 7, 2017

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Senescence of Normal Human Fibroblasts Passaged Beyond 60 Cell Doublings In Cell Culture p. 359 Figure 10.2 The Biology of Cancer (© Garland Science 2007)

News Stories on Cancer: Incidence and Treatment Beads and Cancer Chemotherapy: A Creative Way to Cope with Cancer http://centralny.ynn.com/content/top_stories/537100/a-creative-way-to-cope-with-cancer/ or http://www.youtube.com/watch?v=RDvvu23TUn0 Obesity and Cancer: ABC Evening News, Feb. 16, 2011 http://abcnews.go.com/WNT/video/obesity-crisis-threatens-health-care-system-americans-exercise-food-advice-tips-health-12935370   Obesity and Medical Costs, ABCNEWS, Feb. 16, 2011 ObesityABC16Feb11.doc Colonoscopy: Feb. 22, 2012 http://www.nytimes.com/2012/02/23/health/colonoscopy-prevents-cancer-deaths-study-finds.html?_r=1&hp ColonoscopyNYT_22Feb12.doc Diagnostic Colonoscopy and Polipectomy, Feb. 19, 2013