- Stephen Paget's "Seed and Soil" hypothesis from 1889 proposed that tumor cells ("seeds") need to find a supportive microenvironment ("soil") to grow in. The molecular characteristics of the tumor microenvironment ("soil") are less understood than those of the tumor cells ("seeds"). - The tumor microenvironment consists of various cell types like fibroblasts, immune cells, and endothelial cells as well as the extracellular matrix. It plays an important role in regulating normal cell behavior but can shift to a growth-promoting state and support tumor development. - Chronic inflammation can override the protective constraints of the microenvironment and promote a growth-supporting state through cells like tumor-associated macrophages that secrete factors influencing angiogenesis,

2. • Stephen Paget in 1889 proposed the “Seed & Soil” Hypothesis:
“Tumor cells like seeds are carried in all directions; but they can only live and
grow if they fall on congenial soil”
• Currently, the molecular characteristics of the seeds are much understood
than those of the soil!
• A tumor is much more than clusters of transformed cells standing alone.

3. Tumor Cells Stroma
(harboring genetic mutations) Cells and connective tissue that provides
contextual framework for an organ or tissue
-Epithelial 1) Cells (activated and/or recruited
to the local microenvironment)
-Mesenchymal
-Fibroblasts/Myofibroblasts
-Hematopoietic
-Endothelial Cells
-Myoepithelial Cells
-Innate & adaptive immune cells
2) ECM

4.  Tightly controlled balance of cell proliferation
and death, is achieved and maintained through
intercellular communication
 Important regulator of normal cell behaviour
and tissue homeostasis is the surrounding ECM
(mediated by tight junction proteins and CAMs
such as β1 integrins & epithelial (E)-cadherin)
 Studies indicated that the embryonic micro-
environment is potent in its ability to reprogramme
various cancer cells, including metastatic cells, to a
less aggressive phenotype
 Co-culture experiments showed that normal
fibroblasts prevented the growth of initiated
prostatic epithelial cells

5. During early tumor development, however, the protective
constraints of the microenvironment are overridden by
conditions such as chronic inflammation, and the local tissue
microenvironment shifts to a growth-promoting state
Rous was the first to recognize that
cancers develop from “sub-threshold
neoplastic states” caused by
inherited mutations or following
somatic mutation of critical genes
following viral or chemical
carcinogen exposure.
“Initiation” is irreversible and
persists in otherwise normal tissue
until nonspecific stimulation
“promotion” occurs, typically
following exposure of initiated cells
to chemical irritants or from
exposure to factors released at sites
of chronic inflammation.

7. Among the stromal cell types
that have been implicated in
tumor promotion:
• Endothelial cells
• Fibroblasts
• Pericytes
• BMDCs “
macrophages, neutrophils, ma
st cells, mesenchymal stem
cells MSC …etc”

8. The inflammatory component of a developing neoplasm includes a diverse population
of leukocytes (tumor cells modify certain inflammatory cell types to render them tumor
promoting rather than tumor suppressive)
All of which are loaded with an assorted array of chemokines, cytokines, cytotoxic
mediators including reactive oxygen species, metalloproteases and soluble mediators
of cell killing and cell proliferation, such as tumor necrosis factor
(TNF), interleukins, and interferons
Together they create a microenvironment favoring cell proliferation, genomic
instability, and expansion of cell populations into ectopic tissue
microenvironments, i.e., malignant conversion and cancer development
TAMs may subvert normal macrophage-associated developmental processes and aid in
the invasion of neoplastic cells into surrounding stroma or in the direct remodeling of
stroma  angiogenic and/or lymphangiogenic responses

9. • TAMs secrete VEGF and
interluekin-8 (IL-8) which
are angiogenic, and
epidermal growth factor
(EGF) which is mitogenic
for tumor cells expressing
EGF receptor
• TAMs secrete matrix
metalloproteinases, which
help to carve out room for
tumor expansion, and
release depots of growth
factors from the ECM

10. One of the mechanisms involved in TAM-enhancement of cancer
cell invasion:
involves a paracrine loop in which epidermal growth factor (EGF) produced by TAMs
increases the invasiveness and migration of neighboring cancer cells that express the
EGF receptor (EGFR)
Cancer cells in turn express CSF1, a
potent chemo-attractant and
chemokinetic molecule for CSF1R-
expressing TAMs
Additional paracrine loops exist
between cancer cells expressing
CXC chemokine receptor 4 (CXCR4)
and stromal cells, such as
fibroblasts and pericytes, producing
the cognate ligand stromal cell-
derived factor 1 (SDF1, also known
as CXCL12), which contribute to
directional cancer cell migration

11.  In tumors, under the influence of TGF-β & PDGF, normal fibroblasts are transformed
into myofibroblasts (peritumoral fibroblasts, reactive stromal cells, carcinoma-
associated fibroblasts (CAFs))
 Higher proliferative index (vs normal), expressing α-SMA, surrounded by dense
accumulation of fibrillar collagens “desmoplasia” and is associated with the recruitment
of inflammatory cells and activation of angiogenic programs
 CAFs send signals that either
initiate abnormal epithelial
growth or enhance the
progression of nontumorigenic
cells to tumorigenic states
 CAFs release increased levels
of SDF-1

12. (a)Normal mammary gland duct system, lined by epithelial cells and underlying myoepithelial cells
(arrow heads). Ducts are surrounded by dense fibrous interlobular adipose tissue (at). (b) Ductal
carcinoma in situ disorganization of ductal epithelium (∗) stromal infiltration of inflammatory cells
(arrow)in dense collagenous stroma are evident. (c) Mammary carcinoma in which ductal epithelial
cells(∗) form aberrant glandular structures and grow in cords without gland formation, surrounded
by dense collagen bundles produced by activated fibroblasts.

13.  These cells line the walls of capillaries and larger blood vessels, and lymphatic ducts
 Their growth is encouraged by angiogenic factors (VEGF)
• Endothelial cells release PDGF to attract pericytes
which support the endothelium with VEGF and ANG-
1  structural stability & ability to resist the forces
of the blood pressure
• In tumors, VEGF stimulation without normal
balance of other factors, such as ANG-1 and -
2, capillaries seem unable to attract pericytes and
smooth muscle cells to make well-
constructed, physiologically responsive structures Normal Tumor

14. Normal Dysplasia Carcinoma
The leakiness of tumor
vasculature (red-dextran)
leakiness allows deposition of
fibrin bundles throughout the
tissue

15. The gaps between cells in tumor capillaries allow leakage of fluid into the tumor
tissue. This results in the increase in fibrin deposits within the tumor described
earlier, and a higher interstitial pressure within the tumor, making delivery of
anticancer agents more difficult.