A Zebrafish Model Discovers a Novel Mechanism of Stromal Fibroblast-Mediated Cancer Metastasis

Abstract

Cancer metastasis can occur at the early stage of tumor development when a primary tumor is at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAF) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes. Multicolor-coded cancer cells and CAFs were coimplanted into the transparent zebrafish body and metastasis at a single-cell level was monitored in living animals. Healthy fibroblasts, tumor factor-educated fibroblasts, and CAFs isolated from various tumors were tested for their ability to facilitate metastasis. We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor was at the microscopic size consisting of a few hundred cells, CAFs were able to hijack cancer cells for dissemination from the primary site. Surprisingly, a majority of metastatic cancer cells remained in tight association with CAFs in the circulation. Furthermore, stimulation of non-metastasis-promoting normal fibroblasts with TGF-B, FGF-2, HGF, and PDGF-BB led to acquisition of their metastatic capacity. Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred cells. CAFs are the key cellular determinant for metastasis. Our findings provide novel mechanistic insights on CAFs in promoting cancer metastasis and targeting CAFs for cancer therapy should be aimed at the early stage during cancer development. .

Podoplanin: An emerging cancer biomarker and therapeutic target

“…However, direct, functional assessment of drug responses on primary patient‐derived tumor cells gives the most accurate information on whether the patient will respond to the tested drugs. For example, zebrafish tumor xenograft platforms allow human tumor samples to be grafted into zebrafish embryos, where their growth as primary tumors and their dissemination to distal regions can be determined in the presence or absence of drugs . This platform has been used to demonstrate efficacy of the anti‐PDPN compounds, including MASL on oral squamous cell carcinoma and melanoma xenografts .…”

“…For example, zebrafish tumor xenograft platforms allow human tumor samples to be grafted into zebrafish embryos, where their growth as primary tumors and their dissemination to distal regions can be determined in the presence or absence of drugs. [66][67][68] This platform has been used to demonstrate efficacy of the anti-PDPN compounds, including MASL on oral squamous cell carcinoma and melanoma xenografts. 17,27 This approach can be used to gather critical information that can be reported back to oncologists in charge of treatment planning in less than 5 days after surgery.…”

Early Metastasis in Colorectal Cancer Poses an Option for New Diagnostic and Treatment Strategies

“…The pro-invasion morphological changes induced in CRC cells upon contact with CAFs supernatant confirm the multi-functional role they play in metastasis [45]. A recent study showed that CAFs were able to induce metastasis at a very early stage in tumor development, even when the tumor was of microscopic size, in a small number of cancer cells which remained associated with CAFs upon entering the circulation, potentially forming micrometastatic niches in distal organs which are only visible upon progression [46]. These mechanisms that induce tumor cell invasion and migration may be an interesting target for novel therapies in order to inhibit metastasis.…”

“…Countless studies have shown that homing and extravasation might be more than simply a mechanical response to a faulty environment. TAMs were shown to secrete TNF-α, VEGF and TGF-β into the circulation to distal tissues where they activate tissue macrophage production of S100A8, which is a chemoattractant for CTCs [46]. CTC attachment to the endothelium is allowed by endothelial cell P-and E-selectins binding to tumor cells as well as tumor glycan patterns and adhesion molecule interactions such as integrin and CD44 interactions [73].…”

Morphine alters the circulating proteolytic profile in mice: functional consequences on cellular migration and invasion

“…In support of this possibility, it has been shown that the concentration of the broad-spectrum MMP inhibitor, MMI270, that was required to reduce the invasion of LECs was 100-fold higher than that required to decrease invasion of Lewis lung carcinoma cells (31). Stromal cells regulate cancer cell invasion and metastasis via multiple mechanisms (32)(33)(34), including MMP-9 modulation (9,35).…”