Astrocytic IGFBP2 and CHI3L1 in cerebrospinal fluid drive cortical metastasis of HER2+breast cancer

• Published in: Clinical & experimental metastasis Vol. 37; no. 3; pp. 401 - 412
• Main Authors: Ansari, Khairul I., Bhan, Arunoday, Liu, Xueli, Chen, Mike Y., Jandial, Rahul
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-06-2020; Springer Nature B.V
• Subjects: Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Astrocytes - pathology; Biomedical and Life Sciences; Biomedicine; Brain; Brain cancer; Brain Neoplasms - cerebrospinal fluid; Brain Neoplasms - drug therapy; Brain Neoplasms - secondary; Breast cancer; Breast Neoplasms - cerebrospinal fluid; Breast Neoplasms - pathology; Cancer Research; Cell interactions; Cell proliferation; Cell Proliferation - drug effects; Cerebral Cortex - pathology; Cerebrospinal fluid; Cerebrospinal Fluid - cytology; Chitinase-3-Like Protein 1 - antagonists & inhibitors; Chitinase-3-Like Protein 1 - metabolism; Coculture Techniques; Epidermal growth factor; ErbB-2 protein; Female; Growth factors; Hematology; Humans; In vivo methods and tests; Insulin-Like Growth Factor Binding Protein 2 - antagonists & inhibitors; Insulin-Like Growth Factor Binding Protein 2 - metabolism; Insulin-like growth factor-binding protein 2; Localization; Metastases; Metastasis; Mice; Oncology; Paracrine Communication; Paracrine signalling; Primary Cell Culture; Proteomics; Receptor, ErbB-2 - metabolism; Research Paper; Signal Transduction - drug effects; Surgical Oncology; Tumor cells; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; CHI3LI; HER2; Cortical metastases; IGFBP2; Breast cancer brain metastasis
• ISSN: 0262-0898; 1573-7276
• DOI: 10.1007/s10585-020-10032-4

The brain is often reported as the first site of recurrence among breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Although most HER2+tumors metastasize to the subcortical region of the brain, a subset develops in the cortical region. We hypothesize that factors in cerebrospinal fluid (CSF) play a critical role in the adaptation, proliferation, and establishment of cortical metastases. We established novel cell lines using patient biopsies to model breast cancer cortical and subcortical metastases. We assessed the localization and growth of these cells in vivo and proliferation and apoptosis in vitro under various conditions. Proteomic analysis of human CSF identified astrocyte-derived factors that support the proliferation of cortical metastases, and we used neutralizing antibodies to test the effects of inhibiting these factors both in vivo and in vitro. The cortical breast cancer brain metastatic cells exhibited greater proliferation than subcortical breast cancer brain metastatic cells in CSF containing several growth factors that nourish both the CNS and tumor cells. Specifically, the astrocytic paracrine factors IGFBP2 and CHI3LI promoted the proliferation of cortical metastatic cells and the formation of metastatic lesions. Disruption of these factors suppressed astrocyte-tumor cell interactions in vitro and the growth of cortical tumors in vivo. Our findings suggest that inhibition of IGFBP2 and CHI3LI signaling, in addition to existing treatment modalities, may be an effective therapeutic strategy targeting breast cancer cortical metastasis.