Stromal fibroblasts induce metastatic tumor cell clusters via epithelial–mesenchymal plasticity

Matsumura, Yuko; Ito, Yasuhiko; Mezawa, Yoshihiro; Sulidan, Kaidiliayi; Daigo, Yataro; Hiraga, Toru; Mogushi, Kaoru; Wali, Nadila; Suzuki, Hiromu; Itoh, Takahiko; Miyagi, Yohei; Yokose, Tomoyuki; Shimizu, Satoru; Takano, Atsushi; Terao, Yasuhisa; Saeki, Harumi; Ozawa, Masayuki; Abe, Masaaki; Takeda, Satoru; Okumura, Ko; Habu, Sonoko; Hino, Okio; Takeda, Kazuyoshi; Hamada, Michiaki; Orimo, Akira

doi:10.26508/lsa.201900425

Cited by 48 publications

(73 citation statements)

References 69 publications

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“…1c), consistent with a previous report indicating partial EMT induced in the breast, head and neck cancer cells to be associated with the tumor stroma. 27,54 However, ZEB1 staining was also detected in tumor cells that are not adjacent to the stroma in some PDXs (P10, P21 and P38) with abundant ZEB1 expression ( Fig. 1d).…”

Section: Discussionmentioning

confidence: 96%

“…However, roles of EMT in the tumor cell clusters involved in metastasis formation remain unknown. Studies focusing on collective cancer cell migration have also depended mostly on specific cultured cell lines and experimental murine tumors, while investigations using human clinical materials are rare . The cellular and molecular mechanisms, by which tumor cell clusters invade and seed metastases via EMT, also have not as yet been sufficiently examined using human materials.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, partial EMT contributes to the formation of tumor cell clusters and thereby allows their collective invasion and dissemination. 9,[23][24][25][26][27] However, roles of EMT in the tumor cell clusters involved in metastasis formation remain unknown. Studies focusing on collective cancer cell migration have also depended mostly on specific cultured cell lines and experimental murine tumors, while investigations using human clinical materials are rare.…”

Section: Introductionmentioning

confidence: 99%

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Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Mizukoshi

Okazawa

Haeno

et al. 2019

Intl Journal of Cancer

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Emerging evidence supports the theory that tumor cell clusters efficiently metastasize to distant organs. However, the roles of epithelial‐to‐mesenchymal transition (EMT) in metastasizing tumor cell clusters have not yet been fully elucidated. To investigate this issue, tumor fragments were dissected from 40 colorectal cancer (CRC) patients and implanted subcutaneously into immunodeficient mice. We observed that tumors developed from the tumor fragments obtained from 28 of the 40 CRC patients. The tumors were then dissociated into cell suspensions to be orthotopically injected into secondary mice. The tumors from 13 of the 28 patients progressed. Furthermore, metastases formed spontaneously in the liver and lungs from the tumor fragments obtained from 8 of these 13 patients. Moreover, employing a mathematical analysis, we showed that tumor cell clusters seeded these metastases significantly more often than did single tumor cells. Membrane E‐cadherin‐ and nuclear ZEB1‐positive tumor cells indicating the hybrid epithelial/mesenchymal state were also detected in primary tumors of various CRC patients, and in the corresponding patient‐derived xenografts (PDXs) and circulating tumor cell clusters in the bloodstreams of mice. In contrast, ZEB1 staining was barely detectable in the patient‐matched liver metastases presumably developing through mesenchymal‐to‐epithelial transition. Inhibition of E‐cadherin or ZEB1 expression by shRNA notably prevented the PDX‐derived tumor organoids from colonizing the liver, when injected intrasplenically into mice, indicating E‐cadherin and ZEB1 expressions to be required for their metastatic colonization. Taken together, these findings suggest that the epithelial/mesenchymal state mediates metastatic seeding of human CRC cell clusters into distant organs.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Mizukoshi

Okazawa

Haeno

et al. 2019

Intl Journal of Cancer

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“…Santi et al suggested that cancer and stromal cells of invasive tumors may have been in direct contact and may have established complex crosstalk during tumor development [98]. CAFs induce the formation of metastasizing clusters of tumor cells, with the participation of an intercellular adhesion [103]. According to the authors, CAFs may drive the formation of tumor cell clusters composed of two distinct cancer cell populations, one in a highly epithelial state and another in a hybrid epithelial/mesenchymal state and confer invasive and metastatic traits upon tumor cells.…”

Section: Circulating Cancer Cells Form Clusters Through Tomo-and Hetementioning

confidence: 99%

Are Synapse-Like Structures a Possible Way for Crosstalk of Cancer with Its Microenvironment?

Alekseenko

Чернов

Kostrov

2020

Cancers

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The failure of therapies directed at targets within cancer cells highlight the necessity for a paradigm change in cancer therapy. The attention of researchers has shifted towards the disruption of cancer cell interactions with the tumor microenvironment. A typical example of such a disruption is the immune checkpoint cancer therapy that disrupts interactions between the immune and the cancer cells. The interaction of cancer antigens with T cells occurs in the immunological synapses. This is characterized by several special features, i.e., the proximity of the immune cells and their target cells, strong intercellular adhesion, and secretion of signaling cytokines into the intercellular cleft. Earlier, we hypothesized that the cancer-associated fibroblasts interacting with cancer cells through a synapse-like adhesion might play an important role in cancer tumors. Studies of the interactions between cancer cells and cancer-associated fibroblasts showed that their clusterization on the membrane surface determined their strength and specificity. The hundreds of interacting pairs are involved in the binding that may indicate the formation of synapse-like structures. These interactions may be responsible for successful metastasis of cancer cells, and their identification and disruption may open new therapeutic possibilities.

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“…Besides, CAFs may be involved in tumor cell cluster formation by promoting in a paracrine fashion the invasion of groups of cancer cells, through the induction of EMP. A recent work in breast cancer shows that CAF-released SDF-1 and TGF-β drive the formation and maintenance of a hybrid population of epithelial/mesenchymal (E/M) cells and highly epithelial (E) cells within clusters of cancer cells [ 134 ]. E/M cells are induced by the expression of ZEB1 and lead the collective migration, while E cells, acting as follower cells, preserve cell-cell adhesions that enable cluster formation and show a higher metastatic seeding ability in mouse models [ 134 ].…”

Section: Role Of Cafs In Ctc Cluster Formationmentioning

confidence: 99%

Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs)

Hurtado¹,

Martínez-Pena²,

Piñeiro

2020

Cancers

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The crosstalk between cancer cells and the tumor microenvironment (TME) is a key determinant of cancer metastasis. Cancer-associated fibroblasts (CAFs), one of the main cellular components of TME, promote cancer cell invasion and dissemination through mechanisms including cell-cell interactions and the paracrine secretion of growth factors, cytokines and chemokines. During metastasis, circulating tumor cells (CTCs) are shed from the primary tumor to the bloodstream, where they can be detected as single cells or clusters. The current knowledge about the biology of CTC clusters positions them as key actors in metastasis formation. It also indicates that CTCs do not act alone and that they may be aided by stromal and immune cells, which seem to shape their metastatic potential. Among these cells, CAFs are found associated with CTCs in heterotypic CTC clusters, and their presence seems to increase their metastatic efficiency. In this review, we summarize the current knowledge on the role that CAFs play on metastasis and we discuss their implication on the biogenesis, metastasis-initiating capacity of CTC clusters, and clinical implications. Moreover, we speculate about possible therapeutic strategies aimed to limit the metastatic potential of CTC clusters involving the targeting of CAFs as well as their difficulties and limitations.

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Stromal fibroblasts induce metastatic tumor cell clusters via epithelial–mesenchymal plasticity

Cited by 48 publications

References 69 publications

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Are Synapse-Like Structures a Possible Way for Crosstalk of Cancer with Its Microenvironment?

Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs)

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