Tumor Microenvironment in Breast Cancer—Updates on Therapeutic Implications and Pathologic Assessment

Li, Joshua J.; Tsang, Julia Y. S.; Tse, Gary M.

doi:10.3390/cancers13164233

Cited by 93 publications

(92 citation statements)

References 216 publications

(258 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is also important to consider that other factors may also contribute to the response to the combined inhibition of FAK and mTORC1. These include the potential of hypoxia, other cell types (i.e., adipocytes and myoepithelial cells), and soluble factors (i.e., matrix remodeling enzymes, cytokines, and growth factors) to modulate the ECM [ 84 ].. Discerning the impact of mTORC1 and FAK inhibition on the complex interplay of these factors and their impact on in vivo tumor growth are warranted to discern the potential mechanisms of synergy.…”

Section: Discussionmentioning

confidence: 99%

Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy

Cuellar-Vite

Weber-Bonk

Abdul‐Karim

et al. 2022

Cancers

View full text Add to dashboard Cite

The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that are highly responsive to rapamycin had no impact on tumor growth, FAK inhibition sensitized rapamycin-resistant tumors to mTORC1 inhibition. These data reveal an innate dependency on FAK when mTORC1 signaling is lost in tumors that are resistant to mTORC1 inhibitors. They also suggest a precision medicine approach to improving mTORC1 inhibitor efficacy in resistant cancers by suppressing FAK signaling.

show abstract

Section: Discussionmentioning

confidence: 99%

Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy

Cuellar-Vite

Weber-Bonk

Abdul‐Karim

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…Another important point to consider is the variation in the structure of the tumour microenvironment among different cancers, as it has been shown that tumour microenvironments differ in terms of cell types and the composition of the extracellular matrix [ 75 , 76 , 77 ]. Moreover, crosstalk between MSCs and other cell types in the tumour microenvironment and certain properties of the microenvironment (e.g., pH, O 2 concentration, and ion gradients) importantly affect MSC development and characteristics and the heterogeneity of the population [ 73 , 78 ].…”

Section: The Ambivalent Nature Of Mscs In the Tumour Microenvironmentmentioning

confidence: 99%

Mesenchymal Stem/Stromal Cells May Decrease Success of Cancer Treatment by Inducing Resistance to Chemotherapy in Cancer Cells

Ramuta

Kreft

2022

Cancers

View full text Add to dashboard Cite

The tumour microenvironment, which is comprised of various cell types and the extracellular matrix, substantially impacts tumour initiation, progression, and metastasis. Mesenchymal stem/stromal cells (MSCs) are one of the key stromal cells in the tumour microenvironment, and their interaction with cancer cells results in the transformation of naïve MSCs to tumour-associated MSCs. The latter has an important impact on tumour growth and progression. Recently, it has been shown that they can also contribute to the development of chemoresistance in cancer cells. This review provides an overview of 42 studies published between 1 January 2001 and 1 January 2022 that examined the effect of MSCs on the susceptibility of cancer cells to chemotherapeutics. The studies showed that MSCs affect various signalling pathways in cancer cells, leading to protection against chemotherapy-induced damage. Promising results emerged from the use of inhibitors of various signalling pathways that are affected in cancer cells due to interactions with MSCs in the tumour microenvironment. These studies present a good starting point for the investigation of novel treatment approaches and demonstrate the importance of targeting the stroma in the tumour microenvironment to improve treatment outcomes.

show abstract

“…This is seen though changes to the TME cellular composition, recruiting cells like mesenchymal stem cells, adipose stem cells, dendritic cells and tumour-associated macrophages, all with distinct roles in inflammatory pathways 42 . Latest World Health Organisation (WHO) classification of breast tumours has listed stromal cell response patterns as prognostic factors 43 .…”

Section: The Role Of the Tme In Breast Cancermentioning

confidence: 99%

“…The invasion of tumour-infiltrating lymphocytes was reported as a predictor of survival and response to neoadjuvant treatments, in TNBC and HER2 positive cancer 43 . In comparison, the presence of macrophages was associated with unfavourable prognoses for patient survival 43 .…”

Section: The Role Of the Tme In Breast Cancermentioning

confidence: 99%

See 1 more Smart Citation

'I get by with a little help from my friends': The role of stromal cells in the breast cancer chemoresistance mechanism

Thompson¹

View full text Add to dashboard Cite

Breast cancer is the most common cancer that affects women worldwide, and in New Zealand accounts for 1/3 of new cancer cases. The tumour microenvironment (TME) has an important role in how breast cancer cells respond to chemotherapeutic stress. Mesenchymal stromal cells (MStCs), a component of the TME, have been shown to function in the development of breast cancer cell chemoresistance, promoting survival and more aggressive cancer cell phenotypes. The effect of co-culture on the 4T1 murine breast cancer cell response to chemotherapy has been explored with DNA-damaging therapies but was yet to be explored against other chemotherapeutic mechanisms. Fluorescent-4T1 cells were co-cultured with compact bone-derived MStCs and treated with chemotherapies of differing modalities. Flow cytometry, microscopy and gene expression assays were used to assess the effect of co-culture on the 4T1 response to treatment with clinically relevant chemotherapy drugs. Fluorescent-4T1s had altered morphology, disrupted cell cycles, and decreased viability in response to drug treatment. MStCs had low positive expression of classical stromal markers and had reduced effects of chemotherapy compared to 4T1s. Co-culture with MStCs decreased the effect of drug on 4T1 viability, morphology and cell cycle progression. Increased contact between 4T1s and MStCs resulted in enhanced survival of 4T1 cells under chemotherapeutic stress. These results indicated that drug efficacy is decreased when cancer cells are in co-culture with supporting cells of the TME, independent of the modality of chemotherapeutic stress. This emphasises the importance of the TME to the cancer cell stress response and begins to delve into potential mechanisms for this enhanced interaction. Future research should investigate candidates for inhibiting this interaction between stromal and cancer cells.

show abstract

Tumor Microenvironment in Breast Cancer—Updates on Therapeutic Implications and Pathologic Assessment

Cited by 93 publications

References 216 publications

Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy

Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy

Mesenchymal Stem/Stromal Cells May Decrease Success of Cancer Treatment by Inducing Resistance to Chemotherapy in Cancer Cells

'I get by with a little help from my friends': The role of stromal cells in the breast cancer chemoresistance mechanism

Contact Info

Product

Resources

About