Role of connexins in metastatic breast cancer and melanoma brain colonization

Abstract

SummaryBreast cancer and melanoma cells commonly metastasize to the brain using homing mechanisms that are poorly understood. Cancer patients with brain metastases display poor prognosis and survival due to the lack of effective therapeutics and treatment strategies. Recent work using intravital microscopy and preclinical animal models indicates that metastatic cells colonize the brain, specifically in close contact with the existing brain vasculature. However, it is not known how contact with the vascular niche promotes microtumor formation. Here, we investigate the role of connexins in mediating early events in brain colonization using transparent zebrafish and chicken embryo models of brain metastasis. We provide evidence that breast cancer and melanoma cells utilize connexin gap junction proteins (Cx43, Cx26) to initiate brain metastatic lesion formation in association with the vasculature. RNAi depletion of connexins or pharmacological blocking of connexin-mediated cell-cell communication with carbenoxolone inhibited brain colonization by blocking tumor cell extravasation and blood vessel co-option. Activation of the metastatic gene twist in breast cancer cells increased Cx43 protein expression and gap junction communication, leading to increased extravasation, blood vessel co-option and brain colonization. Conversely, inhibiting twist activity reduced Cx43-mediated gap junction coupling and brain colonization. Database analyses of patient histories revealed increased expression of Cx26 and Cx43 in primary melanoma and breast cancer tumors, respectively, which correlated with increased cancer recurrence and metastasis. Together, our data indicate that Cx43 and Cx26 mediate cancer cell metastasis to the brain and suggest that connexins might be exploited therapeutically to benefit cancer patients with metastatic disease.

754 Connexin 43 expression predicts poor progression-free survival in patients with non-muscle invasive urothelial bladder cancer

“…This could be demonstrated for breast cancer, melanoma and oral squamous cell carcinoma. 25 41 42 As previously published, increased proliferation as assessed by Ki-67 was highly associated with tumour grade, stage and shorter PFS in this cohort. 27 The prognostic role of Ki-67 in urothelial cancer and its association with pathological parameters and prognosis has already been shown in several studies.…”

“…[20][21][22] However, there is growing evidence that Cx43 is involved in cancer development and metastatic processes and overexpressed in invasive lesions of some solid tumours such as breast or colon cancer. [23][24][25] A broad expression analysis of Cx43 in urothelial carcinomas has not been conducted so far and there are no studies available on the prognostic relevance of Cx43 in BC. We aimed to analyse the expression patterns of Cx43 in a fairly large cohort of primary BCs and correlated these to clinicopathological parameters including tumour stage, grade, multifocality, adjacent carcinoma in situ, growth pattern and finally, disease course.…”

Intravital microscopy of cancer: New insights into the spatiotemporal dynamics of the disease

“…Visualization of angiogenesis has also been achieved using quantum dot imaging of tumor vessels. Klemke and colleagues used a transparent zebrafish model to directly visualize the dynamic remodeling of existing blood vessels by cancer cells during angiogenesis and extravasation (20,21) and to elucidate the molecular mechanisms driving metastasis in breast cancer and melanoma (22). Metastasis is a dynamic process, whose spatiotemporal regulation remains poorly characterized.…”

The Role of Astrocytes in Tumor Growth and Progression

“…This chemoprevention role, however, appears to be contact dependent, utilizing gap junctions to mediate the changes in tumor cells. Previously, gap junction proteins Cx43 and Cx26 were utilized by breast cancer and melanoma cells to initiate brain metastatic lesion formation in cohort with the vasculature [170]. Indeed, patient data analysis revealed increased cancer recurrence and metastasis with increased expression of Cx26 and Cx43 in primary melanoma and breast tumor cells.…”