Targeting the tumor microenvironment

Kenny, Paraic A.; Lee, Genee Y.; Bissell, Mina J.

doi:10.2741/2327

Cited by 192 publications

(144 citation statements)

References 63 publications

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“…In contrast to MDCK-Exos, interrogation of the protein profile of 21D1-Exos revealed increased expression of proteases, annexins, integrins, and other secreted proteins associated with the premetastatic niche formation (19,(67)(68)(69)(70)(71)(72)(73)(74), the tumor microenvironment (75) and proteins assisting tissue invasion and metastasis (76,77) (Table II).…”

Section: Exosomes Contain Metastatic Niche Factors Following Oncogenimentioning

confidence: 99%

Oncogenic H-Ras Reprograms Madin-Darby Canine Kidney (MDCK) Cell-derived Exosomal Proteins Following Epithelial-Mesenchymal Transition

Tauro

Mathias

Greening

et al. 2013

Molecular & Cellular Proteomics

171

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Epithelial-mesenchymal transition (EMT) is a highly con- Epithelial-mesenchymal transition (EMT)1 is a cellular process whereby otherwise sessile epithelial cells undergo a shift in plasticity and acquire the ability to disseminate (1-6). Hallmarks of EMT include diminished expression of cell-cell contact and adhesion components (e.g. E-cadherin), diminished expression of cell-matrix components, decreased expression of components involved in cell polarity, elevated expression of proteins involved in cytoskeleton remodelling (e.g. vimentin), and increased expression of various matrix metalloproteinFrom the ‡Department of Biochemistry,

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Section: Exosomes Contain Metastatic Niche Factors Following Oncogenimentioning

confidence: 99%

Oncogenic H-Ras Reprograms Madin-Darby Canine Kidney (MDCK) Cell-derived Exosomal Proteins Following Epithelial-Mesenchymal Transition

Tauro

Mathias

Greening

et al. 2013

Molecular & Cellular Proteomics

171

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“…[1][2][3][4] The ECM is composed of fibers, proteoglycans, hyaluronan (HA) and glycoproteins. It provides rigidity to tumor tissues, and its associated blood vessels nourish cancer cells.…”

mentioning

confidence: 99%

Host stromal versican is essential for cancer‐associated fibroblast function to inhibit cancer growth

Fanhchaksai

Okada

Nagai

et al. 2015

Intl Journal of Cancer

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The stroma provides a microenvironment that regulates tumor cell behavior. The extracellular matrix (ECM) has long been recognized to be important in tumor cell behavior, and previous studies have revealed the impact of individual matrix molecules on tumor progression. Although several reports have highlighted some central roles of tumor cell-expressed versican, the role of host stromal versican is not yet understood. In this study, we demonstrate that versican is an important molecule in the functional ECM structure and maintaining cancer-associated fibroblasts, using versican-negative QRsP11 fibrosarcoma cells. By their subcutaneous injection with cre-expressing adenoviruses to versican-floxed mice, we demonstrate that loss of host stromal versican facilitates tumor cell proliferation, and following angiogenesis, decreases cancer-associated fibroblasts, diminishes collagen fibers and alters hyaluronan distribution, concomitant with upregulation of hyaluronan, TGFb and VEGFmediated signaling. When the versican V3 variant consisting of G1 and G3 domains was expressed in tumor cells, it was integrated into the ECM, regained collagen fibers and cancer-associated fibroblasts and resulted in successful recovery of tumor growth inhibition, indicating that whatever cells produce, the G1 and G3 domains are adequate for versican function. Collectively, our results indicate a dynamic function of versican in the ECM that regulates tumor cell behavior. A greater understanding of the regulation of versican expression may contribute to the development of cancer therapies.Cancer cell behavior is largely affected by its microenvironment (such as the stroma), which comprises the extracellular matrix (ECM), fibroblasts and blood vessels.

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“…In fact, an alternative, emerging therapeutic modality focuses on targeting various microenvironmental processes. 2,32 As the tumor stromal cells are thought to be 'normal' and genetically less labile than the tumor cells proper, resistence to therapy is less likely. Therefore, the tumor stroma may represent an excellent target for directed therapy.…”

Section: Discussionmentioning

confidence: 99%

Stromal signatures in endometrioid endometrial carcinomas

et al. 2014

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The pattern of myometrial invasion in endometrioid endometrial carcinomas varies considerably; ie, from widely scattered glands and cell nests, often associated with a fibromyxoid stromal reaction (desmoplasia) and/ or a lymphocytic infiltrate, to invasive glands with little or no stromal response. Recently, two distinct stromal signatures derived from a macrophage response (colony-stimulating factor 1, CSF1) and a fibroblastic response (desmoid-type fibromatosis, DTF) were identified in breast carcinomas and correlated with clinicopathologic features including outcome. In this study, we explored whether these stromal signatures also apply to endometrioid carcinomas and how their expression patterns correlated with morphologic changes. We studied the stromal signatures both by immunohistochemistry and in situ hybridization in 98 primary endometrioid carcinomas with (87 cases) and without (11 cases) myometrial invasion as well as in the corresponding regional lymph nodes metatases of 9 myoinvasive tumors. Desmoplasia correlated positively with the DTF expression signature. Likewise, mononuclear infiltrates were found in the stroma of tumors expressing CSF1. Twenty-four out of eighty-seven (27%) myoinvasive endometrioid carcinomas were positive for the macrophage signature and thirteen out of eighty-seven (15%) expressed the fibroblast signature. Eleven additional cases were positive for both DTF and CSF1 signatures (11/87; 13%). However, over half of the cases (39/87; 45%) and the majority of the non-myoinvasive tumors (8/11; 73%) failed to express any of the two stromal signatures. The macrophage response (CSF1) was associated with higher tumor grade, lymphovascular invasion, and PIK3CA mutations (Po0.05). There was a concordance in the expression of the CSF1 signature in the primary tumors and their corresponding lymph node metastases. This study is the first characterization of stromal signatures in endometrioid carcinomas. Our findings shed new light on the relationship between genetically different endometrioid carcinomas and various stromal responses. Preservation of the CSF1 macrophage stromal response in the metastases leds support to targeting the CSF1 pathway in endometrioid endometrial carcinomas.

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Targeting the tumor microenvironment

Cited by 192 publications

References 63 publications

Oncogenic H-Ras Reprograms Madin-Darby Canine Kidney (MDCK) Cell-derived Exosomal Proteins Following Epithelial-Mesenchymal Transition

Oncogenic H-Ras Reprograms Madin-Darby Canine Kidney (MDCK) Cell-derived Exosomal Proteins Following Epithelial-Mesenchymal Transition

Host stromal versican is essential for cancer‐associated fibroblast function to inhibit cancer growth

Stromal signatures in endometrioid endometrial carcinomas

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