Inflammation: A driving force speeds cancer metastasis

It has been increasingly recognized that tumor microenvironment plays an important role in carcinogenesis. Inflammatory component is present and contributes to tumor proliferation, angiogenesis, metastasis, and resistance to hormonal and chemotherapy. This review highlights the role of inflammation in the tumor metastasis. We focus on the function of proinflammatory factors, particularly cytokines during tumor metastasis. Understanding of the mechanisms by which inflammation contributes to metastasis will lead to innovative approach for treating cancer.

How tumor spreads remains an enigma and has received great attention in recent years, as metastasis is the major cause of cancer mortality. The complex and highly selective metastatic cascade not only depends on the intrinsic properties of tumor cells but also the microenvironment that they derive from. An inflammatory milieu consisting of infiltrated immune cells and their secretory cytokines, chemokines, and growth factors contribute significantly to the invasive and metastatic traits of cancer cells. Here, we review new insights into the molecular pathways that link inflammation in the tumor microenvironment to metastasis.     

Transient expression of recombinant ACKR4 (CCRL1) gene,an atypical chemokine receptor in human embryonic kidney (HEK 293) cells

ACKR4 also called CCX-CKR, CCRL1 as a member of atypical chemokine receptors, regulates the biological responses by clearance or transporting homeostatic chemokines such as CCL19, CCL21, CCL25, and CXCL13. Since these chemokines are involved in cancer development and metastasis, ACKR4 could have inhibition roles in cancer cell proliferation and invasion. Forming complexes with chemokine receptors by ACKR4 as in the case of hCXCR3 which lead to chemotaxis prevention is the other function of this protein is. However, as an atypical chemokine receptor, ACKR4 is less well-characterized compared to other members. Here, as the first step in understanding the molecular mechanisms of ACKR4 action, transfectants in HEK293T cell, was generated. In this study, ACKR4 coding sequence was cloned and human embryonic kidney 293T cells were used for recombinant production of ACKR4 protein. The liposome-mediated transfection with ACKR4 CDs, were detected in ACKR4 positive cells as early as 48 h post-transfection. The production of ACKR4 protein was confirmed using RT-PCR, dot blot, western blot, and flow cytometry. ACKR4 may represent a novel molecular target in cancer therapy, which might provide a chance for new therapeutic strategy. Therefore, the first step in the understanding of the molecular mechanisms of ACKR4 action is generation ACKR4-HEK293T recombinant cells.     

Role of a metastatic suppressor gene KAI1/CD82 in the diagnosis and prognosis of breast cancer

Globally, breast cancer is the most common type of cancer in females and is one of the leading causes of cancer death in women. The advancement in the targeted therapies and the slight understanding of the molecular cascades of the disease have led to small improvement in the rate of survival of breast cancer patients. However, metastasis and resistance to the current drugs still remain as challenges in the management of breast cancer patients. Metastasis, potentially, leads to failure of the available treatment, and thereby, makes the research on metastatic suppressors a high priority. Tumor metastasis suppressors are several genes and their protein products that have the capability of arresting the metastatic process without affecting the tumor formation. The metastasis suppressors KAI1 (also known as CD82) has been found to inhibit tumor metastasis in various types of solid cancers, including breast cancer. KAI1 was identified as a metastasis suppressor that inhibits the process of metastasis by regulating several mechanisms, including cell motility and invasion, induction of cell senescence, cell–cell adhesion and apoptosis. KAI1 is a member of tetraspanin membrane protein family. It interacts with other tetraspanins, chemokines and integrins to control diverse signaling pathways, which are crucial for protein trafficking and intracellular communication. It follows that better understanding of the molecular events of such genes is needed to develop prognostic biomarkers, and to identify specific therapies for breast cancer patients. This review aims to discuss the role of KAI1/CD82 as a prognosticator in breast cancer.     

Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer

One of the most life-threatening complications of prostate cancer is skeletal metastasis. In order to develop treatment for metastasis, it is important to understand its molecular mechanisms. Our work in this field has drawn parallels between hematopoietic stem cell and prostate cancer homing to the marrow. Our recent work demonstrated that annexin II expressed by osteoblasts and endothelial cells plays a critical role in niche selection. In this study, we demonstrate that annexin II and its receptor play a crucial role in establishing metastasis of prostate cancer. Prostate cancer cell lines migrate toward annexin II and the adhesion of prostate cancer to osteoblasts and endothelial cells was inhibited by annexin II. By blocking annexin II or its receptor in animal models, short-term and long-term localization of prostate cancers are limited. Annexin II may also facilitate the growth of prostate cancer in vitro and in vivo by the MAPK pathway. These data strongly suggest that annexin II and its receptor axis plays a central role in prostate cancer metastasis, and that prostate cancer utilize the hematopoietic stem cell homing mechanisms to gain access to the niche.     

The expression and role of CXC chemokines in colorectal cancer

Cancer is a life-threatening disease world-wide and colorectal cancer is the second common cause of cancer mortality. The interaction between tumor cells and stromal cells plays a crucial role in tumor initiation and progression and is partially mediated by chemokines. Chemokines predominantly participate in the chemoattraction of leukocytes to inflammatory sites. Nowadays, it is clear that CXC chemokines and their receptors (CXCR) may also modulate tumor behavior by several important mechanisms: regulation of angiogenesis, activation of a tumor-specific immune response by attracting leukocytes, stimulation of tumor cell proliferation and metastasis. Here, we review the expression and complex roles of CXC chemokines (CXCL1 to CXCL16) and their receptors (CXCR1 to CXCR6) in colorectal cancer. Overall, increased expression levels of CXC chemokines correlate with poor prognosis.     

MiRNA在乳腺癌转移中的作用

乳腺癌是女性高发的恶性肿瘤之一,远处转移是患者致死的最重要原因。目前乳腺癌转移的具体机制尚未明确。乳腺癌转移相关微RNA(microRNA,miRNA)的发现,为我们研究乳腺癌转移提供了新的思路。miRNA参与包括乳腺癌细胞的生长、凋亡、迁移、侵袭等肿瘤发生、发展过程,进而实现对乳腺癌转移的调控。有些miRNA在乳腺癌转移过程中起促进作用;有些则起抑制作用;还有一些miRNA的功能存在争议。本文将主要着眼于近年来发现的这几类miRNA在乳腺癌转移中所起的作用,并对其将来在乳腺癌诊断、预后判断及治疗中的应用做一综述。     

Positive and negative signaling components involved in TNFalpha-induced NF-kappaB activation

Cell migration is involved in diverse physiological processes including embryogenesis, immunity, and diseases such as cancer and chronic inflammatory disease. The movement of many cell types is directed by extracellular gradients of diffusible chemicals. This phenomenon, referred to as "chemotaxis", was first described in 1888 by Leber who observed the movement of leukocytes toward sites of inflammation. We now know that a large family of small proteins, chemokines, serves as the extracellular signals and a family of G-protein-coupled receptors (GPCRs), chemokine receptors, detects gradients of chemokines and guides cell movement in vivo. Currently, we still know little about the molecular machineries that control chemokine gradient sensing and migration of immune cells. Fortunately, the molecular mechanisms that control these fundamental aspects of chemotaxis appear to be evolutionarily conserved, and studies in lower eukaryotic model systems have allowed us to form concepts, uncover molecular components, develop new techniques, and test models of chemotaxis. These studies have helped our current understanding of this complicated cell behavior. In this review, we wish to mention landmark discoveries in the chemotaxis research field that shaped our current understanding of this fundamental cell behavior and lay out key questions that remain to be addressed in the future.     

Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development

The ability to stimulate angiogenesis/lymphangiogenesis is an intrinsic property of cancer cells, providing them necessary conditions for growth and metastasis. The “angiogenic switch” is one of the earliest consequences of malignant transformation; it involves altered expression of numerous genes and triggers a complex set of signaling pathways in endothelial cells. Processes of tumor microvascular network formation are closely associated with the stages of carcinogenesis (from appearance of benign lesions to invasive forms) and occur with numerous deviations from the norm. Analysis of expression of proangiogenic factors during sequential steps of cervical cancer development (intraepithelial neoplasia, cancer in situ, microinvasive, and invasive cancer) provides opportunity to reconstruct the regulatory mechanisms of angiogenesis/lymphangiogenesis with emphasis on the most important components. This review summarizes literature data on expression of key regulators of angiogenesis in cervical intraepithelial neoplasia and cervical cancer and analyses their possible involvement in molecular mechanisms of neoplastic transformation of epithelial cells, as well as invasion and tumor metastasis. Correlation between expression of proangiogenic molecular factors and various clinicopathological parameters is considered in the context of their possible use in molecular diagnostics and targeted therapy of cervical cancer. Special attention is paid to rather poorly studied regulators of lymphangiogenesis and “non-VEGF dependent,” or alternative, angiogenic pathways that constitute the prospect of future research in the field.     

Immortalization and transformation of human cells

The disruption of homeostatic mechanisms that regulate normal cell growth and proliferation is a hallmark of cancer. Experimentally, many of the same genetic changes that lead to abnormal cell proliferation conspire to confer replicative immortality upon cells in culture. Correspondingly, several lines of evidence implicate cellular immortalization as a prerequisite for cell transformation. Recently much progress has been made in elucidating the cellular machinery that regulates cell lifespan. This review summarizes these recent advances in our understanding of these molecular mechanisms that contribute to human cell immortalization and transformation.     

The regulation of cancer cell death and metabolism by extracellular matrix attachment

The metastasis of cancer cells to distant sites is responsible for the vast majority of cancer mortalities yet the molecular mechanisms underlying this extraordinarily complicated process have yet to be sufficiently elucidated. Recently, it has become clear that cancer cells need to inhibit anoikis, a cell death program induced by loss of attachment to the extracellular matrix (ECM), in order to successfully metastasize. These studies have motivated additional research into the relationship between ECM-detachment and cell viability, much of which reveals integral connections between ECM-detachment and cell metabolism. This review serves to thoroughly discuss the signaling pathways and metabolic changes that are induced by ECM-detachment. In addition, the molecular mechanisms by which cancer cells can alter signaling and metabolism to survive in the absence of ECM-attachment will be highlighted. Furthermore, cell death mechanisms that have been observed or implicated in cells detached from the ECM will also be examined. In aggregate, the studies discussed in this review reveal that ECM-detachment can regulate cancer cell metabolism in a variety of distinct cell types and suggest that interfering with metabolism in ECM-detached cells may be a novel and effective chemotherapeutic approach to selectively inhibit tumor progression.     

The ROCK signaling and breast cancer metastasis

Metastasis is the predominant cause of death in most breast cancer patients. The molecular mechanisms underlying metastasis from primary tumors to distant organs are not clearly characterized. In this review, we depict the role of ROCK signaling in regulating cell motility and growth, and discuss the contribution of this signaling to breast cancer metastasis.     

Molecular mechanisms of ovarian carcinoma metastasis: Key genes and regulatory microRNAs

Metastasis of primary tumors progresses stepwise — from change in biochemistry, morphology, and migratory patterns of tumor cells to the emergence of receptors on their surface that facilitate directional migration to target organs followed by the formation of a specific microenvironment in a target organ that helps attachment and survival of metastatic cells. A set of specific genes and signaling pathways mediate this process under control of microRNA. The molecular mechanisms underlying biological processes associated with tumor metastasis are reviewed in this publication using ovarian cancer, which exhibits high metastatic potential, as an example. Information and data on the genes and regulatory microRNAs involved in the formation of cancer stem cells, epithelial–mesenchymal transition, reducing focal adhesion, degradation of extracellular matrix, increasing migration activity of cancer cells, formation of spheroids, apoptosis, autophagy, angiogenesis, formation of metastases, and development of ascites are presented. Clusters of microRNAs (miR-145, miR-31, miR-506, miR-101) most essential for metastasis of ovarian cancer including the families of microRNAs (miR-200, miR-214, miR-25) with dual role, which is different in different histological types of ovarian cancer, are discussed in detail in a section of the review.     

Exosomes in cancer development,metastasis, and immunity

Exosomes play essential roles in intercellular communications. The exosome was discovered in 1983, when it was found that reticulocytes release 50-nm small vesicles carrying transferrin receptors into the extracellular space. Since then, our understanding of the mechanism and function of the exosome has expanded exponentially that has transformed our perspective of inter-cellular exchanges and the molecular mechanisms that underlie disease progression. Cancer cells generally produce more exosomes than normal cells, and exosomes derived from cancer cells have a strong capacity to modify both local and distant microenvironments. In this review, we summarize the functions of exosomes in cancer development, metastasis, and anti-tumor or pro-tumor immunity, plus their application in cancer treatment and diagnosis/prognosis. Although the exosome field has rapidly advanced, we still do not fully understand the regulation and function of exosomes in detail and still face many challenges in their clinical application. Continued discoveries in this field will bring novel insights on intercellular communications involved in various biological functions and disease progression, thus empowering us to effectively tackle accompanying clinical challenges.     

肿瘤浸润转移分子机制的研究进展

肿瘤浸润转移是多因素参与、多步骤完成的生物化学变化过程。人们已经逐渐认识到浸润转移不仅与肿瘤细胞有关,更是肿瘤细胞和肿瘤组织微环境复杂的相互作用的结果,其过程涉及多个分子作用机制和信号转导途径,包括细胞和细胞的黏附分子、细胞外基质降解、生长因子、趋化因子和淋巴血管生成因子等。本文综述了肿瘤浸润转移的分子机制。     

The organ microenvironment and cancer metastasis

Primary neoplasms are biologically heterogeneous and the process of metastasis consists of a series of sequential, selective steps that few cells can complete. The outcome of cancer metastasis depends on multiple interactions between metastatic cells and homeostatic mechanisms that are unique to one or another organ microenvironment. The specific organ microenvironment determines the extent of cancer cell proliferation, angiogenesis, invasion, and survival. Therapy of metastasis should therefore be targeted not only against tumor cells, but also against the host factors that contribute to and support the progressive growth and survival of metastatic cancer cells.     

Insight of nitric oxide signaling: A potential biomarker with multifaceted complex mechanism in colorectal carcinogenesis

Colorectal carcinogenesis (CRC) is the most important health concerns throughout the World as the tumour cells rapidly spread and abruptly grow in colon and rectum to further organs. Several etiological factors are associated with colorectal carcinogenesis. During invasion and proliferation of tumour cells, various mechanistic molecular pathways are involved in the cells. Nitric Oxide pathway (NO) is one of the important cellular mechanisms associated with tumour cells initiation, invasion and progression. Epidemiological evidences suggest that NO has potential role in development of cancer. The multidisciplinary action of NO on the initiation of cancer depends on several factors including cell type, metastasis stage, and organs involved. This review emphasizes the biological significance of NO in each step of cancer metastasis, its controversial effects for carcinogenesis including initiation, invasion and progression.     

Progress of Breast Cancer basic research in China

Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.     

Specific Pomegranate Juice Components as Potential Inhibitors of Prostate Cancer Metastasis

Pomegranate juice (PJ) is a natural product that inhibits prostate cancer progression. A clinical trial on patients with recurrent prostate cancer resulted in none of the patients progressing to a metastatic stage during the period of the trial. We have previously found that, in addition to causing cell death of hormone-refractory prostate cancer cells, PJ also markedly increases adhesion and decreases migration of the cells that do not die. However, because PJ is a very complex mixture of components and is found in many different formulations, it is important to identify specific components that are effective in inhibiting growth and metastasis. Here, we show that the PJ components luteolin, ellagic acid, and punicic acid together inhibit growth of hormone-dependent and hormone-refractory prostate cancer cells and inhibit their migration and their chemotaxis toward stromal cell-derived factor 1α (SDF1α), a chemokine that is important in prostate cancer metastasis to the bone. These components also increase the expression of cell adhesion genes and decrease expression of genes involved in cell cycle control and cell migration. Furthermore, they increase several well-known tumor-suppression microRNAs (miRNAs), decrease several oncogenic miRNAs, and inhibit the chemokines receptor type 4 (CXCR4)/SDF1α chemotaxis axis. Our results suggest that these components may be more effective in inhibiting prostate cancer growth and metastasis than simply drinking the juice. Chemical modification of these components could further enhance their bioavailability and efficacy of treatment. Moreover, because the mechanisms of metastasis are similar for most cancers, these PJ components may also be effective in the treatment of metastasis of other cancers.     

TLRs: Linking inflammation and breast cancer

Breast cancer is one of the leading causes of mortality in the females. Intensive efforts have been made to understand the molecular mechanisms of pathogenesis of breast cancer. The physiological conditions that lead to tumorigenesis including breast cancer are not well understood. Toll like receptors (TLRs) are essential components of innate immune system that protect the host against bacterial and viral infection. The emerging evidences suggest that TLRs are activated through pathogen associated molecular patterns (PAMPs) as well as endogenous molecules, which lead to the activation of inflammatory pathways. This leads to increased levels of several pro-inflammatory cytokines and chemokines mounting inflammation. Several evidences support the view that chronic inflammation can lead to cancerous condition. Inflammation aids in tumor progression and metastasis. Association of inflammation with breast cancer is emerging. TLR mediated activation of NF-κB and IRF is an essential link connecting inflammation to cancer. The recent reports provide several evidences, which suggest the important role of TLRs in breast cancer pathogenesis and recurrence. The current review focuses on emerging studies suggesting the strong linkages of TLR mediated regulation of inflammation during breast cancer and its metastasis emphasizing the initiation of the systematic study.     

VHL loss of function and its impact on oncogenic signaling networks in clear cell renal cell carcinoma

Loss of von Hippel-Lindau tumor suppressor gene function occurs in familial and most sporadic clear cell renal cell carcinoma, resulting in the aberrant expression of genes that control cell proliferation, metabolism, invasion and angiogenesis. The molecular mechanisms by which loss of function leads to tumorigenesis are not yet fully defined. The von Hippel-Lindau gene product is part of an ubiquitin ligase complex that targets hypoxia inducible factors for polyubiquitination and proteasomal degradation, linking hypoxia response genes to renal cell carcinoma oncogenesis. Loss von Hippel-Lindau gene function also promotes cell invasiveness in response to hepatocyte growth factor, an important regulator of kidney development and renal homeostasis. Increased cell invasiveness is mediated by another ubiquitin ligase target with relevance to the molecular pathogenesis of renal cell carcinoma: beta-catenin. This discovery and other recent insights into kidney cancer oncogenesis implicate convergent developmental and homeostatic signaling pathways in tumorigenesis, tumor invasiveness and metastasis.