Origin of carcinoma associated fibroblasts

The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal-or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by b1 integrin mechanosensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in b1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), b1 expression, and ERK1/2 (pT202/Y204) than ADCTAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or b1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs.Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells.

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“…S4; ref. 26). Nonetheless, these results suggest that TAF accumulation may be driven-at least in partby subtype-specific mechanisms.…”

Section: Resultsmentioning

confidence: 60%

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

Puig

Lugo

Gabasa

et al. 2015

Molecular Cancer Research

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“…3,19 Experimental data demonstrate that MSCs from bone marrow and adipose tissue can efficiently home to tumors, including breast cancer, [20][21][22] where they can stimulate breast cancer growth and invasion, 20,[23][24][25] modulate inflammatory cells within the tumor microenvironment, 26 and give rise to carcinoma-associated fibroblasts. 10,27,28 But only recently have investigations focused on the role of local adipose MSCs on the progression of breast cancer. 3,29 And no study has specifically evaluated the effects of adipose MSCs on the progression of breast cancer resembling the basal-type, which arguably has the most intriguing and complex association with adiposity.…”

Section: Mesenchymal Stem Cells In Mammary Adipose Tissue Stimulate Pmentioning

confidence: 99%

Mesenchymal stem cells in mammary adipose tissue stimulate progression of breast cancer resembling the basal-type

Zhao

Sachs

Wang

et al. 2012

Cancer Biology & Therapy

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“…Ainsi, il y a une sorte d'empreinte de la cellule cancéreuse sur les CAF. La présence de mutations somatiques dans les CAF est discutée [10,11].…”

Section: Constitution Du Stroma Tumoralunclassified

Le stroma tumoral

Buache

Rio

2014

Med Sci (Paris)

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Origin of carcinoma associated fibroblasts

Cited by 105 publications

References 134 publications

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

Mesenchymal stem cells in mammary adipose tissue stimulate progression of breast cancer resembling the basal-type

Le stroma tumoral

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