Mechanical properties of tumors differ substantially from normal cells and tissues. Changes in stiffness or elasticity regulate pro-metastatic behaviors of cancer cells, but effects have been documented predominantly in isolated cells or in vitro cell culture systems. To directly link relative stiffness of tumors to cancer progression, we combined a mouse model of metastatic breast cancer with ex vivo measurements of bulk moduli of freshly excised, intact tumors. We found a high, inverse correlation between bulk modulus of resected tumors and subsequent local recurrence and metastasis. More compliant tumors were associated with more frequent, larger local recurrences and more extensive metastases than mice with relatively stiff tumors. We found that collagen content of resected tumors correlated with bulk modulus values. These data establish that relative differences in tumor stiffness correspond with tumor progression and metastasis, supporting further testing and development of tumor compliance as a prognostic biomarker in breast cancer.
Atypical chemokine receptor CXCR7 (ACKR3) functions as a scavenger receptor for chemokine CXCL12, a molecule that promotes multiple steps in tumor growth and metastasis in breast cancer and multiple other malignancies. While normal vascular endothelium expresses low levels of CXCR7, marked upregulation of CXCR7 occurs in tumor vasculature in breast cancer and other tumors. To investigate effects of endothelial CXCR7 in breast cancer, we conditionally deleted this receptor from vascular endothelium of adult mice, generating CXCR7ΔEND/ΔEND animals. CXCR7ΔEND/ΔEND mice appeared phenotypically normal, although these animals exhibited a modest 35 ± 3% increase in plasma CXCL12 as compared with control. Using two different syngeneic, orthotopic tumor implant models of breast cancer, we discovered that CXCR7ΔEND/ΔEND mice had significantly greater local recurrence of cancer following resection, elevated numbers of circulating tumor cells, and more spontaneous metastases. CXCR7ΔEND/ΔEND mice also showed greater experimental metastases following intracardiac injection of cancer cells. These results establish that endothelial CXCR7 limits breast cancer metastasis at multiple steps in the metastatic cascade, advancing understanding of CXCL12 pathways in tumor environments and informing ongoing drug development targeting CXCR7 in cancer.
Compelling evidence shows that chemokine CXCL12 drives metastasis in multiple malignancies. Similar to other key cytokines in cancer, CXCL12 exists as several isoforms with distinct biophysical properties that may alter signaling and functional outputs. However, effects of CXCL12 isoforms in cancer remain unknown. CXCL12-α, β, and γ showed cell-type specific differences in activating signaling through G protein-dependent pathways in cell-based assays, while CXCL12-γ had greatest effects on recruitment of the adapter protein β-arrestin 2. CXCL12-β and γ also stimulated endothelial tube formation to a greater extent than CXCL12-α. To investigate effects of CXCL12 isoforms on tumor growth and metastasis, we used a mouse xenograft model of metastatic human breast cancer combining CXCR4+ breast cancer cells and mammary fibroblasts secreting an isoform of CXCL12. While all CXCL12 isoforms produced comparable growth of mammary tumors, CXCL12-γ significantly increased metastasis to bone marrow and other sites. Breast cancer cells originating from tumors with CXCL12-γ fibroblasts upregulated RANKL, contributing to bone marrow tropism of metastatic cancer cells. CXCL12-γ was expressed in metastatic tissues in mice, and we also detected CXCL12-γ in malignant pleural effusions from patients with breast cancer. In our mouse model, mammary fibroblasts disseminated to sites of breast cancer metastases, providing another mechanism to increase levels of CXCL12 in metastatic environments. These studies identify CXCL12-γ as a potent pro-metastatic molecule with important implications for cancer biology and effective therapeutic targeting of CXCL12 pathways.
Summary Regional chemotherapy is commonly used to treat patients with colorectal liver metastases. However, improvement in survival has still not been demonstrated. Cytotoxic loaded albumin microspheres for arterial administration have been described as a means of improving the therapeutic index, but their distribution depends upon the prevailing pattern of arterial blood-flow at the time of injection. In this study, the ability of the vasoactive drug angiotensin II to target arterially injected microspheres to colorectal liver metastases is assessed in nine patients using scintigraphic planar and tomographic imaging.The median tumour: normal ratio in nine patients with colorectal liver metastases was 3.4:1 before the administration of angiotensin II. The corresponding ratio after administration of angiotensin II was 7.3:1. The median improvement factor was 1.8 (P <0.05).The data suggest that worthwhile tumour targeting can be achieved with angiotensin II in patients with colorectal liver metastases.Post-mortem studies have shown that up to 70% of patients dying after a potentially curative resection for colorectal cancer, die with liver metastases. The prognosis of patients with colorectal liver metastases is generally poor, survival being in the range of 3 to 9 months (Woods, 1984;Nielsen et al., 1971).Surgical resection of colorectal hepatic metastases may be effective in patients with limited disease (Bradpiece et al., 1987), but may not be feasible in the majority of patients where multiple tumours are present. Although some recent studies of combined systemic 5 fluorouracil and folinic acid or interferon show promising results (O'Connell, 1989;Kerr, 1989;Wadler et al., 1989), conventional systemic chemotherapy has been associated with poor response rates. Attention has therefore turned to regional chemotherapy.It is known that established colorectal liver metastases receive their blood supply from the hepatic artery and the administration of anti-cancer drugs via an indwelling hepatic arterial catheter is now widely practised (Ridge et al., 1987). Unfortunately, although the tumour response rates may increase when chemotherapeutic agents are administered intraarterially rather than systemically (Berger, 1981) a significant increase in survival among treated patients has not been demonstrated by randomised controlled trial (Malik & Wrigley, 1988).Novel chemotherapeutic drug delivery systems including cytotoxic loaded or radioactive microspheres for administration by the arterial route, have been developed. We have previously described cytotoxic loaded albumin microspheres (diameter 20-40IAm) which are trapped in the liver when injected into the hepatic artery (McArdle et al., 1988;Willmott et al., 1985), the drug being released as the microsphere degrades. However intra-arterial injection of such particles results in their unselective distribution throughout the liver, microsphere concentration within different regions of the organ being dependent upon the prevailing distribution of arterial blood-flow. How...
Tumor-initiating cells, also designated as cancer stem cells, are proposed to constitute a subpopulation of malignant cells central to tumorigenesis, metastasis, and treatment resistance. We analyzed activity of the proteasome, the primary organelle for targeted protein degradation, as a marker of tumor- and metastasis-initiating cells. Using human and mouse breast cancer cells expressing a validated fluorescent reporter, we found a small subpopulation of cells with low proteasome activity that divided asymmetrically to produce daughter cells with low or high proteasome activity. Breast cancer cells with low proteasome activity had greater local tumor formation and metastasis in immunocompromised and immunocompetent mice. To allow flexible labeling of cells, we also developed a new proteasome substrate based on HaloTag technology. Patient derived glioblastoma cells with low proteasome activity measured by the HaloTag reporter show key phenotypes associated with tumor-initiating cells, including expression of a stem cell transcription factor, reconstitution of the original starting population, and enhanced neurosphere formation. We also show that patient-derived glioblastoma cells with low proteasome activity have higher frequency of tumor formation in mouse xenografts. These studies support proteasome function as a tool to investigate tumor-and metastasis-initiating cancer cells and potential biomarker for outcomes in patients with several different cancers.
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