1. 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.

2. 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
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
How do cancer cells and cancerous neoplasms grow? (Growth) Chapter 5: Growth Factors and Receptors, pp
How do cancer cells become invasive and become able to spread? (Invasion and Metastasis) Chapter 14: Moving Out: Invasion and Metastasis, pp
What do we study in order to understand metastatic cancers? (Met Models) Chapter 14

3. 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

4. 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

5. What If Different Cancer Cells within the Cancer in a single patient respond differently from one another?
Science, February 1, 2013; Volume 339, pages
“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.

6. What If Different Cancer Cells within the Cancer in a single patient respond differently from one another?
Science, February 1, 2013; Volume 339, pages
“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.

7. 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

8. 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)

9. 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

10. 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

11. 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

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

13. 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

14. 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 The Biology of Cancer (© Garland Science 2007)
p. 422

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

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

19. 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.

20. 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

21. In original Patient
In Nude Mice
In Cell Culture

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

23. TAS = Tumor Associated Stroma
Normal Colon Mucosa
Colon Carcinoma

24. Normal Stromal Stomach Tissue
Adenocarcinoma of Stomach

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

26. Cell Types in the Stroma of Various Human Carcinomas

27. 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

28. 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

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

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

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

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35. 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 ►►
12 Minute Video
Copy this youtube link to your browser

38. End of Heterogeneity Presentation: Tuesday, March 7, 2017

39. Rank
Responses 1 2 3 4 5 6

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

43. News Stories on Cancer: Incidence and Treatment
Beads and Cancer Chemotherapy: A Creative Way to Cope with Cancer or
Obesity and Cancer: ABC Evening News, Feb. 16, 2011
Obesity and Medical Costs, ABCNEWS, Feb. 16, 2011
ObesityABC16Feb11.doc
Colonoscopy: Feb. 22, 2012
ColonoscopyNYT_22Feb12.doc
Diagnostic Colonoscopy and Polipectomy, Feb. 19, 2013