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Stromal Influences on Tumor Formation and Growth. Joshua B Rubin, M.D., Ph.D. Department of Pediatrics Division of Pediatric Hematology/Oncology Washington University School of Medicine. Outline. Historical perspectives on the mechanisms of oncogenesis

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stromal influences on tumor formation and growth

Stromal Influences on Tumor Formation and Growth

Joshua B Rubin, M.D., Ph.D.

Department of Pediatrics

Division of Pediatric Hematology/Oncology

Washington University School of Medicine

outline
Outline
  • Historical perspectives on the mechanisms of oncogenesis
  • Hypothetical roles for stroma in oncogenesis
  • Experimental evidence for stromal action in oncogenesis and tumor growth
  • Stroma in brain tumorigenesis
somatic mutation theory of carcinogenesis
Somatic Mutation Theory of Carcinogenesis
  • Cancer is derived from a single somatic cell that has acquired multiple mutations.

This results in:

    • Activation of proliferation pathways
    • Inactivation of cell cycle inhibitors
    • Inactivation of apoptotic mechanisms
    • Telomere maintenance
    • Activation of migration/invasion pathways
    • Activation of angiogenic mechanisms
support for the somatic mutation theory

Support for the Somatic Mutation Theory

1890: Hansemann notes mitotic abnormalities in cancer cells and postulates that some chromosomes might stimulate proliferation and others might block mitosis.

1914: Boveri observes that specific chromosomal abnormalities are associated with developmental anomalies in sea urchins and proposes that cancer might arise from somatic mutations.

1951: Armitage & Doll postulate the multistage theory of cancer including somatic mutations, genomic rearrangements and changes in tissue interactions.

1960: Nowell & Hungerford discover Philadelphia chromosome (9:22(BCR:ABL)). Soon afterward 8:14 and 8:22 were described (MYC:Ig).

1971: Knudson explains the epidemiology of retinoblastoma in the “two-hit hypothesis” and this work yields the term anti-oncogene or tumor suppressor.

1976: Varmus discovers a cellular homologue (Src) to the transforming protein of Rous Sarcoma Virus, thus identifying the first oncogene.

observations that challenge the primacy of smt

Observations that challenge the primacy of SMT

Stewart (1981) Injection of teratocarcinoma (TC) cells into mouse blastocyst generated normal tissues including germ cells.

DiBeradino (1982) Nuclear transplant from Lucke’s frog renal carcinoma cells into activated Ova produced normal tadpoles.

Martins-Green (1994) Integration of RSV into chicken genome only produced tumors in the setting of inflammation.

slide6

and

Sternlicht (1999) Expression of stromalysin-1 in mammary gland produced epithelial tumors.

Olumi (1999) Xenograft of normal prostatic ECs and myofibroblasts (CAFs) led to intraepithelial neoplasia while co-injection of immortalized, non-transformed ECs and CAFs led to malignancy.

Maffini (2003) Mammary carcinomas in mouse arose after implantation of normal epithelial cells into mutagenized mammary fat pads but not when mutagenized epithelial cells were implanted into control fat pads.

slide8
Paget (1889) Tumor cells are like the seeds of plants, carried by the wind in all directions, but only able to live on congenial soil.

Cancer is a disease of tissue disorganization.

theoretical support for the tissue organization hypothesis

Theoretical support for the tissue organization hypothesis

Inherited cancer predisposition syndromes often result in cancers in a tissue and age restricted fashion.

During normal development organizing centers regulate growth and differentiation.

what constitutes tumor stroma
What constitutes tumor stroma
  • Vascular endothelial cells
  • Fibroblasts
  • Adipocytes
  • Inflammatory cells (mast cells, phagocytes, microglia)
  • Matrix
what kind of roles can we hypothesize for tumor stroma
What kind of roles can we hypothesize for tumor stroma
  • Participant in oncogenesis
  • Regulator of tumor growth
  • Determinant of metastasis
functional interactions between tumor cells and stroma

Functional interactions between tumor cells and stroma

Mueller & Fusenig (2004) Nature Cancer Reviews

three dimensional tissue organization extracellular matrix

Normal breast epithelial cells

In matrigel cultures

T4-2 breast carcinoma cells

In matrigel

T4-2 breast carcinoma cells

with reconstituted alpha-dystroglycan

in matrigel

Three dimensional tissue organization:extracellular matrix

Henry MD, Cohen MB, Campbell KP (2001) Human Pathol 32:791

Muschler J et al. (2002) Cancer Res. 62:7102

the dimensional tissue organization the perivascular niche

DAPI

GFP

CXCl12

The dimensional tissue organization:The Perivascular niche

CXCR4

Properties of brain tumor initiating cells within the perivascular niche

trophic support - Calabrese (2007) Cancer Cell

Increased DNA repair, ABC transporter expression - Bao (2006) Nature

mutational activation of stroma

EC transplant

% tumors

76

NMU

75

0

Veh

0

Mutational activation of stroma

Maffini et al.(2003)J Cell Sci 117:1495-1502

21 days old-remove epithelial cells from mammary glands

52 days old-NMU or vehicle injection

57 days old-NMU or vehicle treated EC transplant

9 month experiment

fibroblasts and driving oncogenesis

NPE

NPE

Tag-HPE

Tag-HPE

Fibroblasts and driving oncogenesis

No tumor

No tumor

Normal fibroblasts

No tumor

Malignant progression

CAFs

Olumi AF et al (1999) Cancer Res. 59:5002

optic pathway glioma formation in nf1

9 months

Nf1 +/- Astro

Nf1 +/- brain

Hyperplasia

Nf1 -/- Astro

Nf1 +/- brain

98% OPGs

Nf1 -/- Astro

Nf1 +/+brain

Hyperplasia

Bajenaru et al. (2003) Cancer Research 63:8573-8577

Nf1flox/flox or Nf1flox/- crossed or not with GFAP-Cre transgenic mice

Optic pathway glioma formation in NF1

developmental regulation of cxcl12 expression in human brain
Developmental regulation of CXCL12 expression in human brain

Warrington et al. (2007) Cancer Research

multiple sources of cxcl12 are present in opg

CXCL12

neurofilament

CXCL12

CD68

pCXCR4

CXCL12

CXCL12

Multiple sources of CXCL12 are present in OPG

Warrington et al. (2007) Cancer Research

cxcl12 stimulates nf1 but not nf1 astrocyte growth in a camp dependent manner

CXCL12

DDA

CXCL12 + - + + - +

FSK - + + - + +

CXCL12 stimulates Nf1-/- but not Nf1+/+ astrocyte growth in a cAMP dependent manner

Warrington et al. (2007) Cancer Research

neurofibromin loss alters cxcr4 mediated camp responses
Neurofibromin loss alters CXCR4-mediated cAMP responses

Warrington et al. (2007) Cancer Research

mutational modulation of stromal response pathways neurofibromin and cxcr4

L12

R4

AC

cAMP

ATP

RAS

growth

L12

R4

P

arrestin

Mutational modulation of stromal response pathways: neurofibromin and CXCR4

NF

Gi

GRKs

growth

conclusions

Conclusions

Carcinogenesis is not always a cell autonomous event.

Abnormal epithelial-stromal interactions can promote tumorigenesis.

Stromal elements represent novel therapeutic targets

thanks to
Thanks to

Washington University

Nicole Warrington

B. Mark Woerner

Lihua Yang

Erin Gribben

Mahil Rao

Shyam Rao

David Gutmann

Arie Perry

Erin Jackson

David Piwnica-Worms