Macrophages promote matrix protrusive and invasive function of breast cancer cells via MIP-1β dependent upregulation of MYO3A gene in breast cancer cells.
The potential of a tumor cell to metastasize profoundly depends on its microenvironment, or "niche" interactions with local components. Tumor-associated-macrophages (TAMs) are the most abundant subpopulation of tumor stroma and represent a key component of tumor microenvironment. The dynamic interaction of cancer cells with neighboring TAMs actively drive cancer progression and metastatic transformation through intercellular signaling networks that need better elucidation. Thus, current study was planned for discerning paracrine communication networks operational between TAMs, and breast cancer cells with special reference to cancer cell invasion and dissemination to distant sites. Here, we report role of MIP-1β in enhancing invasive potential of metastatic breast cancer MDA-MB-231 and MDA-MB-468 cells. In addition, the poorly metastatic MCF-7 cells were also rendered invasive by MIP-1β. The MIP-1β-driven cancer cell invasion was dependent on upregulated expression levels of MYO3A gene, which encodes an unconventional myosin super-family protein harboring a kinase domain. Ex ovo study employing Chick-embryo-model and in vivo Syngenic 4T1/BALB/c mice-model further corroborated aforementioned in vitro findings, thereby substantiating their physiological relevance. Concordantly, human breast cancer specimen exhibited significant association between mRNA expression levels of MIP-1β and MYO3A. Both, MIP-1β and MYO3A exhibited positive correlation with MMP9, an established molecular determinant of cancer cell invasion. Higher expression of these genes correlated with poor survival of breast cancer patients. Collectively, these results point toward so far undisclosed MIP-1β/MYO3A axis being operational during metastasis, wherein macrophage-derived MIP-1β potentiated cancer cell invasion and metastasis via up regulation of MYO3A gene within cancer cells. Our study exposes opportunities for devising potential anti-metastatic strategies for efficient clinical management of breast cancer.
Division of Toxicology, Central Drug Research Institute (CSIR) , Lucknow, Uttar Pradesh, India.
Khemraj Singh
KS
Baghel
Department of Surgical Oncology, King George Medical University , Lucknow, Uttar Pradesh, India.
Brij Nath
BN
Tewari
Division of Toxicology, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh, India; Academy of Scientific and Innovative Research, (AcSIR), New Delhi, India.
Richa
R
Shrivastava
Division of Toxicology, Central Drug Research Institute (CSIR) , Lucknow, Uttar Pradesh, India.
Showkat Ahmad
SA
Malik
Division of Toxicology, Central Drug Research Institute (CSIR) , Lucknow, Uttar Pradesh, India.
Mehraj U-Din
MU
Lone
Division of Toxicology, Central Drug Research Institute (CSIR) , Lucknow, Uttar Pradesh, India.
Nem Kumar
NK
Jain
Division of Toxicology, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh, India; Academy of Scientific and Innovative Research, (AcSIR), New Delhi, India.
Chakrapani
C
Tripathi
Division of Toxicology, Central Drug Research Institute (CSIR) , Lucknow, Uttar Pradesh, India.
Ranjana Kumari
RK
Kanchan
Division of Plant Molecular Biology and Genetic Engineering, National Botanical Research Institute (CSIR) , Lucknow, Uttar Pradesh, India.
Sameer
S
Dixit
Electron Microscopy Unit, Sophisticated Analytical Instrumentation Facility, Central Drug Research Institute (CSIR) , Lucknow, Uttar Pradesh, India.
Kavita
K
Singh
Academy of Scientific and Innovative Research, (AcSIR), New Delhi, India; Electron Microscopy Unit, Sophisticated Analytical Instrumentation Facility, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh, India.
Kalyan
K
Mitra
Academy of Scientific and Innovative Research, (AcSIR), New Delhi, India; Division of Clinical and Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh, India.
Mahendra Pal Singh
MP
Negi
Academy of Scientific and Innovative Research, (AcSIR), New Delhi, India; Division of Clinical and Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh, India.
Mukesh
M
Srivastava
Department of Surgical Oncology, King George Medical University , Lucknow, Uttar Pradesh, India.
Sanjeev
S
Misra
Department of Radiotherapy, King George Medical University , Lucknow, Uttar Pradesh, India.
Madan Lal Brahma
ML
Bhatt
Division of Toxicology, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh, India; Academy of Scientific and Innovative Research, (AcSIR), New Delhi, India.
Smrati
S
Bhadauria
Invadopodia; MIP-1β; MMP-9; MYO3A; invasion; migration