Fibrous stroma: Driver and passenger in cancer development

Our plain-English summary of Fibrous stroma: Driver and passenger in cancer development, by V. Sharma, J. Letson, S. Furuta (Science Signaling, 2022).

The study

• Authors: V. Sharma, J. Letson, S. Furuta
• Journal: Science Signaling
• Published: 2022;15(724):eabg3449
• Type of article: Review
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cumulative evidence shows that fibrogenic stroma and stiff extracellular matrix (ECM) not only result from tumor growth but also play pivotal roles in cellular transformation and tumor initiation. This emerging concept may largely account for the increased cancer risk associated with environmental fibrogenic agents, such as asbestos and silica, and with chronic conditions that are fibrogenic, such as obesity and diabetes. It may also contribute to poor outcomes in patients treated with certain chemotherapeutics that can promote fibrosis, such as bleomycin and methotrexate. Although the mechanistic details of this phenomenon are still being unraveled, we provide an overview of the experimental evidence linking fibrogenic stroma and tumor initiation. In this Review, we will summarize the causes and consequences of fibrous stroma and how this stromal cue is transmitted to the nuclei of parenchymal cells through a physical continuum from the ECM to chromatin, as well as ECM-dependent biochemical signaling that contributes to cellular transformation.

In plain English

This article was a review, not an original study. The authors summarized experimental evidence on fibrous stroma (dense fibrous tissue in an organ) and stiff extracellular matrix (the scaffolding between cells), and on their possible role in starting cancer. They described the cells that build this tissue, myofibroblasts and cancer-associated fibroblasts. They also described how stiff matrix can transmit tension to the cell nucleus, which other studies have linked to uncontrolled growth and genetic damage. Asbestos appeared only briefly. The authors listed environmental agents (asbestos and silica), along with obesity, diabetes and certain chemotherapy drugs, among causes of myofibroblast activation linked to tumor initiation and promotion, citing earlier work. The review reported no asbestos-specific data, fiber types or asbestos-related diseases. The authors concluded that evidence has shown stiff matrix also drives tumor initiation. They speculated that combining a treatment that reduces stromal stiffness with a system that delivers or activates drugs in stiff tissue could possibly be applied to preventing cancers associated with tissue fibrosis or chronic wounds. They said this possibility warrants further investigation. They noted that the mechanistic details are still being unraveled.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published experimental evidence (cell culture, animal and human tissue studies by others); no new data
• Who was studied: No study population; the authors reviewed published experimental evidence linking fibrogenic stroma and tumor initiation
• Exposure: Asbestos is mentioned only in passing, together with silica, as an environmental agent among causes of myofibroblast activation; no fiber types, products, jobs or doses are given
• Main results:
  • The review described evidence (from other studies) that desmoplasia, the formation of fibrous tissue, may come before malignant cells appear rather than only following tumor growth
  • The review listed chronic metabolic disorders (obesity and diabetes), environmental agents (asbestos and silica) and chemotherapeutic drugs (bleomycin, methotrexate and cisplatin) as causes of myofibroblast activation linked to tumor initiation and promotion, citing earlier work; no asbestos data were presented
  • The review cited studies in which stiff matrix with high collagen density alone was enough to induce malignant transformation of cultured normal breast cells
  • The review described how the tension of stiff matrix is transmitted to the nuclear membrane of cells, which the authors linked to genome instability
  • The authors speculated that combining a mechanoresponsive delivery or activation system with a mitigator of stromal stiffness could possibly be applied to preventing cancers associated with tissue fibrosis or chronic wounds. They said this possibility warrants further investigation.
• The authors' conclusion: The authors concluded that fibrous tumor stroma, once thought to be only a consequence of cancer, has been shown by cumulative evidence to also drive tumor initiation
• Limitations the authors state:
  • The authors stated that the mechanistic details of how fibrous stroma leads to tumor initiation are still being unraveled
  • The authors noted that therapies targeting stiff stroma have so far only been used for cancer treatment, not prevention

Topics

Medical terms in this study, explained in our Lexicon: Fibrogenic, Fibrosis.

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