Fibroblasts in cancer

doi:10.1038/NRC1877

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Fibroblasts in cancer

Journal Article•DOI•

Fibroblasts in cancer

Raghu Kalluri¹, Raghu Kalluri², Raghu Kalluri³, Michael Zeisberg²•Institutions (3)

Massachusetts Institute of Technology¹, Harvard University², Beth Israel Deaconess Medical Center³

01 May 2006-Nature Reviews Cancer (Nature Publishing Group)-Vol. 6, Iss: 5, pp 392-401

TL;DR: Fibroblasts are a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.

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Abstract: Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.

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Journal Article•DOI•

Hallmarks of cancer: the next generation.

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Douglas Hanahan¹, Robert A. Weinberg²•Institutions (2)

ISREC¹, Massachusetts Institute of Technology²

04 Mar 2011-Cell

TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

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51,099 citations

Cites background from "Fibroblasts in cancer"

...…Invasion and Metastasis It is increasingly apparent that crosstalk between cancer cells and cells of the neoplastic stroma is involved in the acquired capability for invasive growth and metastasis (Egeblad et al., 2010; Qian and Pollard, 2010; Joyce and Pollard, 2009; Kalluri and Zeisberg, 2006)....
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...Heterotypic Contributions of Stromal Cells to Invasion and Metastasis It is increasingly apparent that crosstalk between cancer cells and cells of the neoplastic stroma is involved in the acquired capability for invasive growth and metastasis (Egeblad et al., 2010; Qian and Pollard, 2010; Joyce and Pollard, 2009; Kalluri and Zeisberg, 2006)....
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...…fibroblasts admixed with cancer cells into mice, and more recently by genetic and pharmacologic perturbation of their functions in tumor-prone mice (Dirat et al., 2010; Pietras and Ostman, 2010; Räsänen and Vaheri, 2010; Shimoda et al., 2010; Kalluri and Zeisberg, 2006; Bhowmick et al., 2004)....
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...Recruited myofibroblasts and reprogrammed variants of normal tissue-derived fibroblastic cells have been demonstrated to enhance tumor phenotypes, notably cancer cell proliferation, angiogenesis, and invasion and metastasis; their tumorpromoting activities have largely been defined by transplantation of cancer-associated fibroblasts admixed with cancer cells into mice, and more recently by genetic and pharmacologic perturbation of their functions in tumor-prone mice (Dirat et al., 2010; Pietras and Ostman, 2010; Räsänen and Vaheri, 2010; Shimoda et al., 2010; Kalluri and Zeisberg, 2006; Bhowmick et al., 2004)....
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Journal Article•DOI•

Microenvironmental regulation of tumor progression and metastasis.

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Daniela F. Quail¹, Johanna A. Joyce¹•Institutions (1)

Memorial Sloan Kettering Cancer Center¹

01 Nov 2013-Nature Medicine

TL;DR: The paradoxical roles of the tumor microenvironment during specific stages of cancer progression and metastasis are discussed, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

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Abstract: Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

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5,396 citations

Journal Article•DOI•

Inferring tumour purity and stromal and immune cell admixture from expression data

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Kosuke Yoshihara¹, Maria Shahmoradgoli², Emmanuel Martinez, Rahulsimham Vegesna², Hoon Kim, Wandaliz Torres-Garcia², Victor Trevino, Hui Shen³, Peter W. Laird³, Douglas A. Levine⁴, Scott L. Carter⁵, Gad Getz⁵, Katherine Stemke-Hale², Gordon B. Mills, Roel G.W. Verhaak - Show less +11 more•Institutions (5)

University of Texas at Austin¹, University of Texas MD Anderson Cancer Center², University of Southern California³, Memorial Sloan Kettering Cancer Center⁴, Broad Institute⁵

11 Oct 2013-Nature Communications

TL;DR: A method that uses gene expression signatures to infer the fraction of stromal and immune cells in tumour samples and prediction accuracy is corroborated using 3,809 transcriptional profiles available elsewhere in the public domain.

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Abstract: Infiltrating stromal and immune cells form the major fraction of normal cells in tumour tissue and not only perturb the tumour signal in molecular studies but also have an important role in cancer biology. Here we describe 'Estimation of STromal and Immune cells in MAlignant Tumours using Expression data' (ESTIMATE)--a method that uses gene expression signatures to infer the fraction of stromal and immune cells in tumour samples. ESTIMATE scores correlate with DNA copy number-based tumour purity across samples from 11 different tumour types, profiled on Agilent, Affymetrix platforms or based on RNA sequencing and available through The Cancer Genome Atlas. The prediction accuracy is further corroborated using 3,809 transcriptional profiles available elsewhere in the public domain. The ESTIMATE method allows consideration of tumour-associated normal cells in genomic and transcriptomic studies. An R-library is available on https://sourceforge.net/projects/estimateproject/.

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4,651 citations

Cites methods from "Fibroblasts in cancer"

...We devised two gene signatures: (1) a ‘stromal signature’ that was designed to capture the presence of stroma in tumour tissue, and (2) an ‘immune signature’ that aimed to represent the infiltration of immune cells in tumour tissue (Supplementary Data 1)....
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...Bladder urothelial carcinoma 122 (95) Breast cancer 530 (488) 774 (723) 515 (482) Colon and rectal adenocarcinoma 224 (218) 83 (81) 264 (255) Glioblastoma multiforme 529 (417) 403 (319) 154 (123) Head and neck squamous cell carcinoma 303 (293) Clear cell renal cell carcinoma 72 (42) 469 (329) 480 (329) Lung adenocarcinoma 230 (228) Lung squamous cell carcinoma 133 (115) 155 (130) 223 (129) 220 (129) Ovarian serous cystadenocarcinoma 585 (469) 558 (442) 262 (248) Uterine corpus endometrial carcinoma 333 (253) 370 (281) Total 1,247 (1,001) 1,942 (1,639) 1,882 (1,515) 2,920 (2,463)...
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Journal Article•DOI•

Cancer Metastasis: Building a Framework

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Gaorav P. Gupta¹, Joan Massagué¹•Institutions (1)

Memorial Sloan Kettering Cancer Center¹

17 Nov 2006-Cell

TL;DR: Understanding of the origins and nature of cancer metastasis and the selection of traits that are advantageous to cancer cells is promoted.

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3,863 citations

Cites background from "Fibroblasts in cancer"

...An area of intense interest, the topic of stromal contributions to cancer, has been covered by several recent reviews (Condeelis and Pollard, 2006; de Visser et al., 2006; Kalluri and Zeisberg, 2006)....
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Journal Article•DOI•

Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment

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Douglas Hanahan¹, Lisa M. Coussens²•Institutions (2)

École Polytechnique Fédérale de Lausanne¹, Oregon Health & Science University²

20 Mar 2012-Cancer Cell

TL;DR: Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types, which presents interesting new targets for anticancer therapy.

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3,486 citations

Cites background from "Fibroblasts in cancer"

...A number of studies have implicated CAFs in the capability to limit the impact on tumor growth and progression of cancer cell apoptosis (Kalluri and Zeisberg, 2006; Loeffler et al., 2006; Pietras and Ostman, 2010)....
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...…as well as a variety of ECM remodeling enzymes that further modify the TME, rendering it more supportive of cancer cell invasion, both proximal to the CAFs as well in adjacent normal tissue (Chaffer and Weinberg, 2011; Cirri and Chiarugi, 2011; Kalluri and Zeisberg, 2006; Pietras and Ostman, 2010)....
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...…normal fibroblasts, CAFs can also produce a variety of ECM-degrading enzymes that release such latent angiogenic factors (bFGF, VEGF, TGF-b), rendering them bioavailable to their receptors on endothelial cells (Kalluri and Zeisberg, 2006; Pietras and Ostman, 2010; Räsänen and Vaheri, 2010)....
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...…factor-1 (SDF-1/CXCL12), and a variety of FGFs—with the capability to stimulate cancer cell proliferation (Cirri and Chiarugi, 2011; Erez et al., 2010; Franco et al., 2010; Kalluri and Zeisberg, 2006; Orimo et al., 2005; Räsänen and Vaheri, 2010; Rosen and MacDougald, 2006; Spaeth et al., 2009)....
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References

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Open Access

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Journal Article•DOI•

The hallmarks of cancer.

[...]

Douglas Hanahan¹, Robert A. Weinberg²•Institutions (2)

University of California, San Francisco¹, Massachusetts Institute of Technology²

07 Jan 2000-Cell

TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.

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28,811 citations

"Fibroblasts in cancer" refers background in this paper

...The tumour stroma In the early growth of tumours, cancer cells form a neoplastic lesion that is embedded in the microenvironment of a given tissue (usually epithelium...
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Journal Article•DOI•

Inflammation and cancer

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Lisa M. Coussens¹, Zena Werb¹•Institutions (1)

University of California, San Francisco¹

19 Dec 2002-Nature

TL;DR: It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration.

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Abstract: Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

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12,395 citations

Journal Article•DOI•

Integrins: versatility, modulation, and signaling in cell adhesion.

[...]

Richard O. Hynes¹•Institutions (1)

Massachusetts Institute of Technology¹

03 Apr 1992-Cell

10,063 citations

"Fibroblasts in cancer" refers background in this paper

...and by direct interactions with cells through integrin...
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Journal Article•DOI•

Tumor Angiogenesis: Therapeutic Implications

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Judah Folkman

18 Nov 1971-The New England Journal of Medicine

TL;DR: This new capillary growth is even more vigorous and continuous than a similar outgrowth of capillary sprouts observed in 2016 and is likely to be accompanied by neovascularization.

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Abstract: THE growth of solid neoplasms is always accompanied by neovascularization. This new capillary growth is even more vigorous and continuous than a similar outgrowth of capillary sprouts observed in f...

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9,874 citations

Additional excerpts

...Tumour progression is clearly dependent on angiogenesi...
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Journal Article•DOI•

Epithelial–mesenchymal transitions in tumour progression

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Jean Paul Thiery¹•Institutions (1)

Curie Institute¹

01 Jun 2002-Nature Reviews Cancer

TL;DR: Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

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Abstract: Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

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6,362 citations