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Tumor Mechanobiology. Focus on the role of the biophysical properties of the ECM in tumor progression A review from the literature. Definition and scales. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells.

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Tumor mechanobiology

Tumor Mechanobiology

Focus on the role of the biophysical properties of the ECM in tumor progression

A review from the literature


Definition and scales
Definition and scales

Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells.

Schrader J. et al., Hepatology. 2011

  • Cellular Mechanobiology

  • Tissue

  • Mechanobiology

  • Molecular/Cellular Mechanotransduction

Cell stiffness,

Cell contractility,

Cell rheology

Matrix stiffness, deformability

ROCK-Driven Actomyosin Contractility Induces Tissue Stiffness and Tumor Growth.

Kümper S and Marshall CJ, Cancer Cell. 2011

Pathak A. et al., PLoS One, 2011

Discher DE. et al. Science, 2005


Tissue rigidity influences cell behavior
Tissue rigidity influences cell behavior

Engler JA. et al., Cell, 2006

Discher DE. et al, Science 2005


Changes in the physical mechanical environment during tumor growth
Changes in the physical/mechanical environment during tumor growth

  • Forces generated by the expanding tumor in a restrictive tissue space

  • Denser/Stiffer tissue that forms around a tumor

  • Increased interstitial pressure and altered fluid flow patterns caused by the growth of new blood vessels

Paszek MJ, et al. J Mammary Gland Biol. and Neoplasia, 2004

Shieh AC. Annals of Biomedical Eng. 2011


Outline
Outline growth

  • Can we use tumor biophysical properties as prognostic or diagnostic tools?

  • How do tumor cells respond to physical/ mechanical changes of the environment?

  • Matrix stiffening: cause or consequence?


Outline1
Outline growth

  • Can we use tumor biophysical properties as prognostic or diagnostic tools?

  • How do tumor cells respond to physical/ mechanical changes of the environment?

  • Matrix stiffening: cause or consequence?


Tumor mechanobiology1
Tumor growthmechanobiology

“The denser the breast/ the liver, the worst the prognosis”

“The stiffer the matrix,

the more aggressive the tumor”

“The denser the breast/the liver, the worst ”

“The stiffer the matrix,

the more aggressive the tumor”

Women who have a breast density of 75 percent or higher on a mammogram have a risk of breast cancer that is four to five times greater than that of women with little or no density, making mammographic breast density one of the strongest biomarkers of breast cancer risk.


Elastography a non invasive method to measure tissue stiffness
Elastography growth: a non-invasive method to measure tissue stiffness

  • Ultrasound or MR-based techniques for measuring stiffness by the difference in the velocity of the elastic shear wave propagation across a given tissue

  • The force is generated by applying pressure.

www.breastcancer.about.com


An increased stiffness is diagnostic of diseased tissue
An increased stiffness is diagnostic of growthdiseased tissue

Normal Liver

Fibrotic Liver

Conventional MRI

Elastogram

(or strain map)

Venkatesh SK, et al. A J Roentgenology. 2008


Increased tissue stiffness can assist intervention and therapeutic decisions biopsy treatment
Increased tissue stiffness can assist intervention and therapeutic decisions: biopsy, treatment

  • Assessing prognosis and candidacy for treatment in patients with chronic liver disease.

  • Spare patients that don’t need it the discomfort and risk of complications associated with liver biopsy

Yin et al,. ClinGastroenterolHepatol. 2007


An increased stiffness is prognostic of disease outcome
An increased stiffness is prognostic of therapeutic decisions: biopsy, treatmentdisease outcome


An increased stiffness is diagnostic of breast tumor lesions
An increased stiffness is diagnostic of breast tumor lesions therapeutic decisions: biopsy, treatment

Breast Fibroadenoma

Invasive Lobular Carcinoma

Ultrasound Elastography

X-Ray Mammography

When a mechanical compression or vibration is applied, the tumor deforms less than the surrounding tissue i.e. the strain in the tumor is less than the surrounding tissue.


Collagen density promotes mammary tumor initiation and progression
Collagen density promotes mammary tumor initiation and progression

Abstract

Background: Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen.

  • Model system:

    Col1a1tmJae mouse crossed with MMTV-PyMT mouse

     double-transgenic tumor model with increased stromal collagen in mouse mammary tissue.

Provenzano P .et al., BMC Medicine, 2008.


Increased stromal collagen in mouse mammary tissue significantly increases tumor formation
Increased progressionstromal collagen in mouse mammary tissue significantly increases tumor formation

10 week-old mice; Collagen staining: Picrosirius red

Provenzano P et al., BMC Medicine, 2008


Increased stromal collagen in mouse mammary tissue significantly increases metastasis formation
Increased progressionstromal collagen in mouse mammary tissue significantly increases metastasis formation

Provenzano P et al., BMC Medicine, 2008


Definition of tumor associated collagen signatures
Definition of tumor-associated collagen signatures progression

TACS-3:radially aligned collagen fibers, correlates with local invasion of tumor cells

Provenzano P et al., BMC Medicine, 2008


Can these tumor associated collagen signatures be used as a prognostic marker
Can these “tumor-associated collagen signatures” be used as a prognostic marker?

  • The relative concentration of collagen and the orientation of fibers with respect to epithelial cells was assessed using SHG imaging on 196 biopsies.

  •  Statistical score was developed to determine :

  • whether TACS-3 is present in clinical histopathology samples from patients

  • - whether TACS3 correlated with patient survival

Yes!

Yes!

Conklin, MW. Et al., AJP, 2011


Outline2
Outline as a prognostic marker?

  • Can we use tumor biophysical properties as prognostic or diagnostic tools?

  • How do tumor cells respond to physical/ mechanical changes of the environment?

  • Matrix stiffening: cause or consequence?

Yes!


Outline3
Outline as a prognostic marker?

  • Can we use tumor biophysical properties as prognostic or diagnostic tools?

  • How do tumor cells respond to physical/ mechanical changes of the environment?

  • Matrix stiffening: cause or consequence?



Tumor cells but nor normal cells stiffen in response to stiffer environment
Tumor cells but nor normal cells stiffen in response to stiffer environment

  • Technique: Particle-tracking microrheology (PTMR)

    • Tracking the Brownian motions of individual tracer beads embedded within the cells using ballistic particle delivery system

    • The particles motion reflect the intracellular viscoelasticity of the cells.

  • MCF10A possessing ErbB2 transforming potential stiffen (G’p) in response to elevated matrix stiffness (G’c), whereas non-transformed MECs don’t

  • Increased intracellular stiffening correlated with a more motile phenotype

Baker EL. et al., Biophys. J., 2010


Matrix rigidity modulates tumor cell proliferation morphology and migration
Matrix rigidity modulates tumor cell proliferation, morphology and migration

  • Technique:96-well plate system that arrays colI-conjugated PA gels that increase in stiffness by at least 50-fold across the plate

Tilghman R. et al., PLoS One, 2010


Matrix rigidity modulates tumor cell proliferation morphology and migration 2
Matrix rigidity modulates tumor cell proliferation, morphology and migration (2)

A549 cells

Tilghman R. et al., PLoS One, 2010


Stiffness and adhesivness modulate tumor cell mechanotransduction and migration
Stiffness and morphology and adhesivness modulate tumor cell mechanotransduction and migration

  • On stiff ECMs, more protrusive adhesions are stabilized due to higher Rho and Rac activation levels, leading to maximal stress fiber contractility, and rear adhesions progress through the initiation-rupture cycle rapidly. Both of these promote higher migration speeds

Pathak A. and Kumar S., PLoS One, 2011


Stiffness and adhesivness modulate tumor cell mechanotransduction and migration 2
Stiffness and morphology and adhesivness modulate tumor cell mechanotransduction and migration (2)

  • Lower ligand-density surfaces require higher ECM elasticities to reach the maximum migration speed, whereas higher ligand-density surfaces enhance migration speed on relatively soft ECMs.

Pathak A. and Kumar S., PLoS One, 2011


Matrix rigidity governs the formation of invadopodia
Matrix rigidity governs the formation of morphology and invadopodia

 On hard PA, invasive MCF10ACA1d produced more invadopodia and degraded more ECM than on soft PA.

Alexander NR. et al., Current Biol. 2008


Cell, 2009 morphology and

 Model: MMTV-Neu


Mammary glands conditioned with lox expressing fibroblasts were stiffer and promoted tumor growth
Mammary glands morphology and conditioned with LOX expressing fibroblasts were stiffer and promoted tumor growth

1) LOX conditioning of the mammary gland results in more fibrillar collagen and more linearizedcollagen.

2) LOX-conditioned mammary gland favors tumor progression

  •  Signaling:

  • IntegrinClustering

  • Enhancement of PI3K Signaling

Levental KR et al., Cell, 2009


Cancer patients expressing high levels of lox have poor outcome
Cancer patients expressing high levels of LOX have morphology and poor outcome

Breast Cancer Patients

(ER neg.)

H&N Cancer Patients

Erler J et al., Nature, 2006


Inhibition of lox decreased metastasis formation in vivo
Inhibition of LOX decreased metastasis formation morphology and in vivo

  • Model: Orthotopic injection of MDA-MB-231

  • in the mammary fat pad of nude mice.

Erler J et al., Nature, 2006



Outline4
Outline tumor?

  • Can we use tumor biophysical properties as prognostic or diagnostic tools?

  • How do tumor cells respond to physical/ mechanical changes of the environment?

  • Matrix stiffening: cause or consequence?


Can the physical properties of the 3d environment act as an initiating event of tumorigenesis
Can the physical properties of the 3D environment act as an initiating event of tumorigenesis?

  • Question: What is the impact of mechanical stimulation on the initiation of colon cancer.

  • Model System:

    • Colon explants

    • The deformation of the tissue induced by compression was observed by two-photon excitation (2PEF) microscopy of the endogenous tissue fluorescence

Whitehead J. et al., HFSP Journal, 2008


Myc and twist1 expression is induced by mechanical stimulation of apc deficient but not wt colon
Myc initiating event of and Twist1 expression is induced by mechanical stimulation of APC deficient but not WT colon

Whitehead J. et al., HFSP Journal, 2008


B catenin nuclear translocation is induced by mechanical stimulation of apc 1638n but not wt colon
b initiating event of -catenin nuclear translocation is induced by mechanical stimulation of APC1638N/+ but not WT colon

 When APC is limiting, mechanical strain (intestinal transit or tumor growth), can be interpreted by cells of preneoplastic colon tissue as a signal to initiate a b-catenin dependent transcriptional program characteristic of cancer.

Whitehead J. et al., HFSP Journal, 2008


Remodeling of the ecm is in part induced by the tumor cells
Remodeling of the ECM is in part induced by the tumor cells initiating event of

1.

2. Secretion of ECM remodeling enzymes: transglutaminases, lysyloxidases, etc.

3. Role of the stromal cells in environment remodeling.

Before, after or in synergy with the tumor cell-induced remodeling


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