Review Article Research advances of secretory proteins in malignant tumors Na Zhang, Jiajie Hao, Yan Cai, Mingrong Wang State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China Correspondence to: Mingrong Wang. State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Email: [email protected]; Jiajie Hao. State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Email: [email protected]. Abstract Secretory proteins in tumor tissues are important components of the tumor microenvironment. Secretory proteins act on tumor cells or stromal cells or mediate interactions between tumor cells and stromal cells, thereby affecting tumor progression and clinical treatment efficacy. In this paper, recent research advances in secretory proteins in malignant tumors are reviewed. Keywords: Secretory protein; tumor microenvironment; stromal cells; tumor progression; drug resistance Submitted Aug 26, 2020. Accepted for publication Jan 05, 2021. doi: 10.21147/j.issn.1000-9604.2021.01.12 View this article at: https://doi.org/10.21147/j.issn.1000-9604.2021.01.12 Introduction breast cancer, colorectal cancer, glioma, ovarian cancer, osteosarcoma, pancreatic cancer, etc. Secretory proteins can be produced by tumor cells or stromal cells. Secretory proteins from tumor cells may act Enhancement of tumor cell proliferation, stemness and on tumor cells through autocrine or paracrine mechanisms survival by tumor cell-secreted proteins and may also act on stromal cells. Secretory proteins produced by stromal cells may mediate the regulation of Intercellular communication is important for maintaining stromal cells on tumor cells. As important components of cell proliferation, stemness and survival. Secretory proteins the tumor microenvironment, secretory proteins promote are important mediators of intercellular signal transduction between tumor cells. or inhibit tumor progression and affect sensitivity to cancer therapy. The secretory protein regenerating islet-derived protein IV (Reg IV) is a member of the Reg multigene family that Secretory proteins mediate regulation activates epidermal growth factor receptor (EGFR)/ between tumor cells AKT/AP-1 signaling to increase the expression of Bcl-2, Bcl-XL and Survivin, thereby promoting the proliferation Tumor cells may secrete growth factors, glycoproteins, of colorectal adenocarcinoma cells (1). Secreted Meprin α, inflammatory cytokines, enzymes and exosomes, which can an astacin-type metalloprotease with proteolytic enzyme act on the cells that produce them or adjacent tumor cells. activity, promotes epidermal growth factor (EGF) and There are an increasing number of studies on regulation transforming growth factor alpha (TGF-α) shedding from between tumor cells mediated by secretory proteins, and the plasma membrane and releasing into the extracellular this regulation has been found to be involved in an matrix (ECM), thereby promoting the proliferation and increasing number of cancer types, including lung cancer, migration of colorectal cancer cells by activating the © Chinese Journal of Cancer Research. All rights reserved. www.cjcrcn.org Chin J Cancer Res 2021;33(1):115-132 116 Zhang et al. Secretory proteins in malignant tumors EGFR/ERK1/2 pathway (2). Similarly, rhomboid domain- breast cancer cells overexpressing hypoxia-inducible factor containing protein 1 (RHBDD1), a rhomboid 1-alpha (HIF-1α) protects tumor cells from hypoxia- intramembrane serine protease, interacts with proTGF-α induced cell death by directly activating LRP1/AKT to induce cleavage and a disintegrin and metalloproteinase signaling (13). HSP90 binds to and stabilizes the protein (ADAM)-independent secretion of TGF-α and subsequent kinase D2 (PRKD2) in human cancer cells. Inhibition of activation of the EGFR/Raf/MEK/ERK pathway to HSP90 triggers the degradation of PRKD2, promoting promote the proliferation and growth of colorectal cancer apoptosis in cancer cells. The ectopic expression of PRKD2 cells (3). The M2 isoform of pyruvate kinase (PKM2) partially restores HIF-1α and secretes vascular endothelial promotes the proliferation of triple-negative breast cancer growth factor A (VEGFA) levels in hypoxic cancer cells, cells by inducing EGFR phosphorylation (4). protecting cancer cells treated with HSP90 inhibitors from Secreted interleukin-8 (IL-8) stimulates ovarian cancer apoptosis effects and restoring the formation of blood cell proliferation and alters cell cycle distribution by vessel (14). The autocrine-paracrine loop of tumor necrosis increasing cyclin D1 and cyclin B1 expression as well as factor α (TNF α) participates in the constitutive activation activating the phosphatidylinositol 3-kinase (PI3K)/AKT of transcription factors NF-κB and YY1 in prostate cancer and Raf/MEK/ERK pathways (5). Autocrine parathyroid cells, resulting in the inhibition of Fas expression and hormone-related protein (PTHLH) promotes the cancer cell resistance to FasL-induced apoptosis (15). C-C proliferation and growth of intrahepatic cholangio- motif chemokine ligands (CCLs) contribute to the carcinoma cells by activating both the ERK/ATF-2/cyclin resistance of prostate cancer cells to castration through an D1 and JNK/ATF-2/cyclin D1 pathways (6). In cervical autocrine manner. The CCL2/CCR2 pathway reduces the cancer, expression and secretion of growth/differentiation cleavages of caspase-3 and poly ADP-ribose polymerase factor 15 (GDF15) gradually increases with tumor (PARP) to decrease the apoptosis of cancer cells induced by progression, and GDF15 acts on the cell membrane cabazitaxel. Blockade of CCL2/CCR2 pathway combined receptor ErbB2 to activate PI3K/AKT and mitogen- with cabazitaxel may be a potential strategy for the activated protein kinases/extracellular signal-regulated treatment of castration-resistant prostate cancer (16). kinase (MAPK/ERK) signaling, which upregulates cyclin Promoting effect of secretory proteins from tumor cells on D1 and cyclin E1 and downregulates p21 to promote tumor cell motility and metastasis tumor cell proliferation (7). Annexin A1 (ANXA1) highly expressed and secreted by triple-negative breast cancer cells Secretory proteins also play important roles in tumor cell enhances the proliferation, survival and invasive capacity of invasion, migration and tumor metastasis. breast cancer cells through the ANXA1/FPR1 pathway (8). PKM2 secreted by lung cancer cells directly acts on Progranulin (PGRN) increases proliferation and promotes integrin β1 to activate the FAK/SRC/ERK axis, thereby the dedifferentiation of breast cancer stem cells via the upregulating the expression of matrix metalloproteinase-9 receptor Sortilin (9). (MMP-9) and promoting lung cancer metastasis (17). The The autocrine/paracrine insulin-like growth factor 2 lung cancer cell secreted glycoprotein signal peptide, CUB (IGF2)/IGF1R cycle plays an important role in maintaining and EGF-like domain-containing protein 3 (SCUBE3) is proliferation and the stem cell-like characteristics induced cleaved by matrix metalloproteinase-2 (MMP-2) and by the fusion gene CD74-NRG1 in non-small cell lung MMP-9 into an N-terminal EGF-like domain and a C- cancer (NSCLC) (10). The receptor protein KIT is highly terminal CUB domain. Both SCUBE3 and the CUB expressed in colon cancer under hypoxic conditions, and domain can bind to TGFBR2 on the surface of cancer cells stem cell factor (SCF) secreted from differentiated tumor and further activate TGFBR1 to phosphorylate mothers cells binds to KIT on undifferentiated stem-like tumor cells against decapentaplegic homolog 2/3 (SMAD2/3) and then to maintain their proliferation and clonogenic capacity (11). promote the transcription of Snail, Slug, plasminogen Autotaxin secreted by ovarian cancer stem cells promotes activator inhibitor-1 (PAI-1), MMP-2, MMP-9 and VEGF, the secretion of lysophosphatidic acid (LPA), which in turn thereby enhancing the epithelial mesenchymal transition maintains cellular proliferation and stemness through (EMT), invasion and metastasis of the cells (18). IL-8 also LPA/LPAR1/AKT1 signaling (12). promotes the invasion of ovarian cancer cells by Heat shock protein HSP 90-alpha (Hsp90α) secreted by upregulating the expression of MMP-2 and MMP-9 (5). © Chinese Journal of Cancer Research. All rights reserved. www.cjcrcn.org Chin J Cancer Res 2021;33(1):115-132 Chinese Journal of Cancer Research, Vol 33, No 1 February 2021 117 EGFRvIII-positive cells in glioblastoma (GBM) secrete than PTEN due to the utilization of different initiation epidermal growth factor-like protein 7 (EGFL7) and codons during PTEN gene translation. It is a secretory and further promote the expression of EGFL7 in EGFR wild- membrane-permeable lipid phosphatase. PTEN-long type (EGFRwt) cell by directly activating the EGFR inhibits the PI3K pathway in tumor cells, inducing cell pathway and enhancing the invasion and migration of death in vitro and in vivo (27). EGFRwt cells (19). Secreted EGFL7 from pituitary Secreted frizzled