The Role of Tumor Stroma in Cancer Progression and Prognosis: Emphasis on Carcinoma-Associated Fibroblasts and Non-small Cell Lung Cancer

Abstract

Maintenance of both normal epithelial tissues and their malignant counterparts is supported by the host tissue stroma. The tumor stroma mainly consists of the basement membrane, fibroblasts, extracellular matrix, immune cells, and vasculature. Although most host cells in the stroma possess certain tumor-suppressing abilities, the stroma will change during malignancy and eventually promote growth, invasion, and metastasis. Stromal changes at the invasion front include the appearance of carcinoma-associated fibroblasts (CAFs). CAFs constitute a major portion of the reactive tumor stroma and play a crucial role in tumor progression. The main precursors of CAFs are normal fibroblasts, and the transdifferentiation of fibroblasts to CAFs is driven to a great extent by cancer-derived cytokines such as transforming growth factor-β. During recent years, the crosstalk between the cancer cells and the tumor stroma, highly responsible for the progression of tumors and their metastasis, has been increasingly unveiled. A better understanding of the host stroma contribution to cancer progression will increase our knowledge about the growth promoting signaling pathways and hopefully lead to novel therapeutic interventions targeting the tumor stroma. This review reports novel data on the essential crosstalk between cancer cells and cells of the tumor stroma, with an emphasis on the role played by CAFs. Furthermore, it presents recent literature on relevant tumor stroma- and CAF-related research in non-small cell lung cancer.

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

“…Moreover, the effect of matrix stiffening on fibroblast density was dominant or comparable with that due to mitogenic cues present in serum up to 0.5% FBS, which is a more physiologic concentration than the 10% to 20% FBS used in many cell culture studies. All these findings strongly support that matrix stiffening alone may be as important as soluble growth factors in driving fibroblast accumulation in vivo, thereby challenging the current view of stromagenesis as driven by paracrine signaling only (3,(8)(9)(10). Moreover, they extend previous evidence of a positive feedback loop in which activated fibroblasts lay out increased amounts of fibrotic ECM components that render a stiffer ECM, which in turn may drive fibroblast activation and accumulation further (11,14).…”

“…The current paradigm of TAF accumulation based on repairlike processes (3,(8)(9)(10)) supports a therapeutic strategy to reduce their density based on inhibiting stromal growth factors. Our data support the latter strategy in ADC-TAFs but not in SCC-TAFs.…”

“…In NSCLC and other cancer types, TAFs are frequently found in an activated/myofibroblastlike phenotype that is roughly characterized by the expression of alpha-smooth muscle actin (a-SMA) and the enhanced deposition of fibrotic ECM components. In the current paradigm, TAF accumulation is assumed to be largely driven by paracrine signals secreted by cancer cells or infiltrated immune cells as in generic repair processes (3,(8)(9)(10). However, two lines of evidence suggest that mechanical cues provided by the abnormal tissue hardening of desmoplastic tumors may also contribute to TAF accumulation.…”

Magnetic Nanoparticles for Precision Oncology: Theranostic Magnetic Iron Oxide Nanoparticles for Image-Guided and Targeted Cancer Therapy

“…Tumor stroma also serves as a drug delivery barrier. Without the ability to overcome the tumor stromal barrier, the majority of delivered nanoparticles are sequestered at the perivascular areas [101]. To overcome the physical barrier of the stroma in drug delivery, theranostic nanoparticles targeting uPAR that is highly expressed in both cancer cells and tumor-associated stromal cells have been developed and their antitumor effects have been examined in a human pancreatic cancer xenograft model in nude mice.…”

RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation

“…Reactive stroma is found in most cancers and is typified by the coevolution of myofibroblasts (5)(6)(7). Importantly, the volume of reactive stroma relative to cancer is predictive of the rate of cancer progression in several tumor types (8)(9)(10)(11)(12)(13)(14)(15). Furthermore, in vivo modeling has shown that reactive stroma is tumor-promoting (16)(17)(18)(19).…”