This document provides an overview of cancer mechanisms for researchers. It describes: 1) The histology and pathology of cancerous tumors, how they differ from normal tissue, and tumor staging. 2) The multistep process of carcinogenesis from initiation by carcinogens to metastasis, and how cancer hijacks normal processes like tissue renewal. 3) The cancer stem cell model which suggests that only a small subset of cancer cells can self-renew and may be responsible for tumor growth; this provides opportunities for new therapies. 4) The importance of understanding cancer as a systemic process rather than just targeting genes or pathways in isolation.

1. What is Cancer, anyway?
A biological overview of the
mechanisms of malignancy for
computational and system biology
researchers
Pedro Romero, PhD.
School of Informatics
Center for Computational Biology and Bioinformatics
Indiana University - Indianapolis

2. The “main source”
The Biological Basis of Cancer
Robert G. McKinnell, Ralph E. Parchment,
Alan O. Perantoni, G. Barry Pierce
2nd. Ed. 2006
Cambridge University Press

3. Outline
• The Pathology of cancer
• The development of cancer
• The stem cell model of tissue renewal
• Stem cancer cell or cancer stem cell?
• The Importance of a “Systemic” View

4. The Pathology of Cancer
What is cancer and what it
looks like

5. Some Histology
Parenchyma:
Functional part of
an organ
Stroma:
connective, non-
functional
supportive
framework of a
biological cell,
tissue, or organ
Cancerous
tumors also
consist of
parenchyma
and stromaProstate tissue

6. Some Histology
Parenchymal
cells synthesize
angiogenic
factors that
induce the host
to supply
supportive
stromal tissue
for it, including
fibroblasts and
vascular cells
Prostate tissue

7. More Histology
Self-renewing tissue
consists of stem, or
progenitor, cells (basal
layer, arrow) and normal,
differentiated cells
(superficial layer: notice
lack of nuclei in keratin
cells).
When normal cells die, stem
cells divide in a controlled
manner to replace them.
Stems cells divide
asymmetrically into a new
stem cell and a normal,
differentiating, cell.
Normal squamous epithelium of skin

8. Altered states
• Tissue changes:
– Hyperplasia: Reversible tissue growth caused by
environmental stimuli (e.g., hormones: Breasts enlarge
during pregnancy and nursing) Cells grow in size and/or
number. (Atrophy is the opposite effect)
– Metaplasia: Reversible changes in differentiation caused by
environmental stimuli (e.g., change from epithelial to
squamous cells in lungs due to smoke)
– Dysplasia: (Still) Reversible changes in normal maturation
of cells due to persistent stimuli – cells differentiate poorly
and can become malignant with prolonged exposure.
– Neoplasia: Irreversible changes in cell proliferation and
maturation that persist after the stimulus has disappeared.
Neoplasms = Tumors (can be malignant). When restricted to
one location and separated from stromal tissue, the
neoplasm is said to be in situ (non invasive).

9. Altered states
Dysplasia of squamous
epithelium of skin: Notice
poorly differentiated cells:
Instead of orderly
differentiation of basal
cells into keratin, we see
undifferentiated cells in
the keratin layer
Dysplastic squamous epithelium of skin

10. Altered states
Carcinoma in situ: No
differentiation between
basal (arrow) and
superficial layer is evident
Lung squamous cell carcinoma in situ

11. Tumors: Good and Bad
• Benign tumors:
– Slow growing neoplasms
– Designated by tissue + suffix -oma
– Well differentiated cells (rare cell division)
– Similar to normal tissue
– Secretes same proteins, but can do so in
uncontrolled fashion
– Excessive growth can push and compromise
adjacent tissue

12. Tumors: Good and Bad
• Malignant tumors:
– Neoplasms with malignant tendencies:
• Uncontrolled growth
• Invasion of normal tissue
• Metastasis → Host death
– Malignant cells:
• Pleomorphic (varied size/shape)
• Anaplastic (undifferentiated)
• Atypical nuclei / High nucleus-cytoplasm ratio
• Can also excrete proteins and other molecules as
normal tissue → Potential tumor markers

13. Tumors: Good and Bad
• Malignant tumors nomenclature (suffixes):
– Epithelial: -carcinoma,
– Mesenchymal (bone, fat, cartilage): -sarcoma
– Embrionic/Child: -blastoma
– Other:
• Glioma (brain)
• Lymphoma (lymphocytes, always malignant)
• Seminoma (germ cells)
• Skin pigmented cells or melanocytes (melanoma)
• Leukemias

14. Tumors: Good and Bad
• Malignant tumor nomenclature (examples):

15. Benign tumors
Lipoma of intestine. Notice
appearance similar to
normal fat tissue (yellow
center).

16. Benign tumors
Left: Leiomyomas of the uterus (Uterine
fibroids). These are well defined nodules of
the uterus muscular wall.
Below: Tissue comparison between a
leiomyoma (left) and a leiomyosarcoma
(malignant, right). Notice well differenciated
cells vs. anaplastic cells.

17. Malignant tumors
Squamous cell carcinoma
of the bronchus (lungs).
Notice differences
between normal tissue
(right side) and anaplastic
cells on the left.

18. Tumor staging
Overall Stage Grouping is also referred to as Roman
Numeral Staging. This system uses numerals I, II, III,
and IV (plus the 0) to describe the progression of cancer.
• Stage 0 carcinoma in situ.
• Stage I cancers are localized to one part of the body.
• Stage II cancers are locally advanced, as are Stage III cancers.
Whether a cancer is designated as Stage II or Stage III can
depend on the specific type of cancer.
• Stage IV cancers have often metastasized, or spread to other
organs or throughout the body.
• A cancer may also be designated as recurrent, meaning that it
has appeared again after being in remission or after all visible
tumor has been eliminated. Recurrence can either be local,
meaning that it appears in the same location as the original, or
distant, meaning that it appears in a different part of the body.

19. Cancer as a “caricature” of normal
tissue renewal

20. The Development of Cancer
From carcinogenesis to
metastasis: The dangerous life
and evolution of “bad” cells

21. The processes of cancer
• Carcinogenesis
– Initiation: Carcinogen modifies DNA
– Latency: Period between initiation and tumor formation. Need
appropriate environment (promoters) to express phenotype
– Promotion: Application of promoters and other environmental
factors leads to tumor formation. Tumors regress when
promoters are removed.
– Progression: Evolution towards autonomous stage
(independence from environmental factors)
– Conversion: Malignant neoplastic phenotype
• Metastasis
• Malignant cell dissemination. Requires autonomous cells
with special abilities (i.e., converted cells)

22. Carcinogenesis
• Initiation
–Chemicals
–Radiation
–Virus
–Endogenous processes

23. Initiation
• Chemical carcinogenesis
– Carcinogens usually interact with DNA and
generate “adducts” that cause copy errors
– Some carcinogens act directly, some have to
be metabolized first into an “active” form
– Not all carcinogens are mutagenic, and not all
mutagenic substances are carcinogenic
– Exogenous
• Man-made
• Naturally occurring
– Endogenous
• Free radicals

24. Initiation
• Chemical carcinogenesis example

25. Promotion
• Promoters are usually not genotoxic, as
opposed to carcinogens
• Promotion seems to be an epigenetic process
related to gene expression and regulation
• Promoters believed to stimulate growth and
prevent apoptosis / differentiation in initiated
cells
• Promoter presence induces proliferation of
initiated cells into tumors
• Withdrawal of promoter at this stage results in
complete regression of these lesions

26. Promotion
• Chemical promoters
– Exogenous
– Endogenous (hormones, growth factors)
• Promotion processes
– Hyperplasia (selective proliferation)
– Reduction of tissue regulation on initiated cell
• Cytotoxicity (kill surrounding normal cells)
• Inhibition of inter-cellular communication
– Cytotoxicity also promotes growth factor activity
needed for cell repair, which helps proliferation

27. Progression
• Progression enhances aggressiveness of tumor
cells and lead to autonomous cells through
different routes:
– Defects in apoptosis
– Increase in proliferative cell population
– Decrease of tendency to terminally differentiate
– Shift towards autonomous growth
– Genetic instability
– Invasive metastatic behaviors
• Cells show great heterogeneity, which is
gradually reduced through selection

28. Conversion
• At the end of the progression phase, cells
have converted to the malignant
phenotype
– Invasive
– Highly autonomous
– Can erode tissue barriers
– Can escape both physical and regulatory
constraints from surrounding normal tissue

29. Metastasis
• The metastatic cascade
– Disruption of basal membrane
– Cell detachment (separation)
– Cell motility
– Invasion
– Penetration of vascular system
– Circulating cancer cells
– Arrest (stasis)
– Extravasion and proloferation

30. The metastatic
cascade

32. Disruption of basal membrane and
stroma invasion
• Basal membrane separates epithelium from stromal
extracellular matrix (ECM)
• Controlled enzymatic digestion of ECM components is a
major step in metastasis
– Type IV collagen-degrading enzymes for basal membrane
– Type I collagenase for stromal tissue
– Other proteolytic enzymes for digestion of fibronectin, elastin,
proteoglycans, among others
– Matrix metalloproteinases (MMP) can degrade any proteins in
the ECM. Elevated MMP activity always found in malignant
tissue
– Cathepsins hydrolize peptide bonds
– Enzyme inhibitors are promising anti-metastatic agents

33. Cell detachment
• Reduced cohesion is essential
• Expression of E-cadherin is essential for
conservation of normal epithelial
morphology and non-invasive phenotype
• Lack of E-cadherin produces loss of
morphology and invasiveness
• Transfection of malignant cells with E-
cadherin cDNA blocks invasion
• Detachment is critical for metastasis

34. Cell detachment
Coman, 1944
Normal lip cells Squamous carcinoma lip cells

35. Cell Motility
• “Amoeboid” motility of cancer cells first reported by
Virchow in 1863. Confirmed in vitro in 1939 and 1950,
and in vivo in 1998
• Cells have to migrate individually
• Embryonic cells also have the ability to migrate
• Autocrine motility factor (AMF) and its receptor (AMF-R)
stimulate motility. Their expression in malignant tissue
correlates with aggressiveness
• The tubulin-based cytoplasmic microtubule complex
(CMTC) is implicated in directional migration
• Agents that depolymerize microtubules inhibit invasion
(vinca alkaloids and nocodazole)

36. Penetration of vascular system
(Intravasion)
• Invading cells move towards capillaries and
lymphatic vessels in ECM with the help of
digestion enzymes
• Density of capillaries in a tumor is positively
correlated with metastatic behavior
• Newly formed blood vessels have small defects
(gaps and membrane discontinuities)
• Type IV collagenase helps breach capillary
membranes
• Most cells are damaged or destroyed upon
entrance to the circulation

37. Penetration of vascular system
(Intravasion)
Cancer cell penetrating
the lumen of a capillary
vessel through a process
called diapedesis. Here it
penetrates through a gap
between endothelial cells
(arrow)
Song, et al 1986.

38. Stabilization with
fibrin
Arrest (stasis)
Angiogenesis

39. Can normal tissue
“metastasize?”
(Left) Chick embryo
cells become
undifferentiated and
migrate to generate
new tissues during
development
The metastatic
process is already
encoded in our DNA

40. The Stem Cell Model of
Tissue Renewal
Avenues for potential therapies

41. Stem cell-based tissue renewal

42. Stem cell-based tissue renewal

43. Therapy through control of trophic
factors

44. Therapy through control of
differentiation factors

45. Therapy through destruction of
malignant differentiated cells

46. Stem cancer cell or cancer
stem cell?
Well… both!

47. Cancer vs stem cell

48. Cancer stem cells?

49. Stem cell model revisited… almost

50. The Importance of a
“Systemic” View
Parting Thoughts

51. Cancer is a natural selection
process
• Cancer is based on mutations, but not those
which generate new abilities, but mainly those
which access potential abilities
• Many of these abilities are expressed in
embryonic cells during early development
• Mutations allow for selectively turning “on” and
“off” specific processes.
• Genes involved are oncogenes and tumor
supressor genes

52. Understanding cancer provides
“systemic” view
• Framework for molecular studies of cancer
– Oncogenes
– Cancer related pathways
• Metabolic
• Regulatory
• Signaling
– Cancer related protein interactions
– Put all these in relation to the cancer process as
a whole
– Do not just target genes or pathways: attack
processes or at least be aware of them!

53. Understanding cancer provides
“systemic” view
Initiation Promotion Progression Conversion Metastasis

54. THANKS!