Hindawi Publishing CorporationInternational Journal of Breast CancerVolume 2012, Article ID 756257, 3 pagesdoi:10.1155/2012/756257

Editorial 

The Influence of the CancerMicroenvironment onthe Process ofMetastasis

 AndraR. Frost,1 Douglas R.Hurst,1 LalitaA. Shevde,2 and Rajeev S. Samant2

1 Department of Pathology, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294-1170, USA 2 Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile,

 AL 36604, USA

Correspondence should be addressed to Andra R. Frost, afrost@uab.edu

Received 26 February 2012; Accepted 26 February 2012

Copyright © 2012 Andra R. Frost et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Metastasis of breast cancer is a multistep process that requirescancer cells to invade stroma at the primary site, gain accessto vasculature, survive in the circulation, extravasate into theparenchyma of the secondary site, and survive and proliferateat the secondary site. During each of these steps, themicroenvironment surrounding the cancer cells is believedto be an active participant. The cancer microenvironmentalso varies during the metastatic process. At the primary tumor in the breast, invasive cancer cells are surrounded by fibroblasts, extracellular matrix (ECM), cellular constituentsof the vasculature, inflammatory/immune cells, and adiposetissue. Metastasizing cancer cells are exposed to a completely diff erent microenvironment within the circulatory system.The cancer microenvironment at the secondary site is, again,very diff erent from the microenvironment of the breast andvaries depending on the sites of metastasis. At the primary and metastatic sites, the interaction between tumor cellsand their surrounding milieu is reciprocal; the tumor cellsinfluence the stroma and vice versa, ultimately fueling tumorprogression. The papers in this issue discuss the dynamicsof the interactions of tumor cells and their microenviron-ment, detailing how tumor cells manipulate their milieuand, conversely, how the reactive tumor microenvironmentinfluences tumor cell plasticity, invasion, metastasis, andcancer therapy.

Z. I. Khamis et al. provide a thorough summary of theroles of the tumor stroma and tumor microenvironment inthe various steps involved in the metastatic process, as wellas in the development of breast cancer in their paper “Activeroles of tumor stroma in breast cancer metastasis.” The authors

discuss research findings related to the contribution of vari-ous constituents of the tumor microenvironment, includinginflammatory cells, fibroblasts, extracellular matrix, andblood vessels, in the metastatic process. They also include adiscussion of the signaling pathways utilized by cancer cellsto modify the stroma and ECM. This review serves as anexcellent overview for this issue.

Two papers in this issue discuss the cancer cells them-selves and how characteristics or functions of the cancercells influence the tumor microenvironment. Just as themicroenvironment signals to the cancer cells, the cancer cellsalter the microenvironment to promote tumor progressionand metastasis. J. E. Chu and A. L. Allan in their paper“The role of cancer stem cells in the organ tropism of breast cancer metastasis: a mechanistic balance between the “seed”and the “soil?”” have exhaustively summarized the role of thecancer stem cells in determining the organ tropism exhibitedby breast cancer cells. Given the fact that metastasis is aninefficient process, the authors make a compelling case forcancer stem cells to be the rare population that is equippedwith the necessary armamentarium of traits to successfully metastasize. The paper summarizes the hierarchical roleof cancer stem cells within the various subtypes of breastcancer and the phenotypic and functional signatures of breast cancer stem cells. It also puts into perspective theorigin of cancer stem cells and their role in conditioning thepremetastatic niche. The authors also provide a detailed anal- ysis of the microenvironment of the various metastatic nichesencountered by metastatic breast cancer cells, specifically the bone, brain, lungs, liver, and lymph nodes. The paper

 

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concludes with a stimulating discussion on the contributionof cancer stem cells to therapeutic resistance taking intoaccount the interactions of the cancer stem cells with themicroenvironment.

The review by J. Alsarraj and K. W. Hunter, “Bro-modomain-containing protein 4: a dynamic regulator of breast cancer metastasis through modulation of the extracel-lular matrix ”, is focused on the activity of bromodomain-containing protein 4 (BRD4) in breast cancer cells. BRD4functions as an inherited susceptibility gene for breast cancerprogression and metastasis and regulates the transcription of select genes through epigenetic mechanisms. Multiple ECMgenes are regulated by BRD4 that may lead to changes in theoverall structure of the surrounding environment or alter thecell-matrix interactions to promote breast cancer invasionand metastasis.

The roles of estrogen receptor (ER) signaling and sig-naling through Toll-like receptors (TLR) in the crosstalkand interactions of breast cancer cells with the tumormicroenvironment are the topics of another two papersin this issue. Hormones play a critical role in directingbreast cancer progression. Specifically, ER signaling is oneof the critical and complex determinants of breast cancermetastasis. S. S. Roy and R. K. Vadlamudi have provided anintegrated picture of this specific signaling in the paper “ Roleof estrogen receptor signaling in breast cancer metastasis”. They emphasize the importance of ER-coregulatory proteins andtheir misexpression in promoting metastasis of ER-positivebreast cancer cells. They have discussed possible therapeutictargets to block ER-driven metastasis. Most significantly, thispaper brings to notice the importance of defining alternativesignaling pathways. Specifically, multiple signaling pathwaysin addition to estrogen signaling are involved in activatingERs. Hence, combination therapies using both endocrineand nonendocrine agents that block these diff erent pathwaysmay have better therapeutic eff ects and may delay metastasis.

D. Bhattacharya and N. Yusuf discuss the data regardingTLR expression in breast cancer and its role in inflamma-tion and cell survival in the tumor microenvironment in“Expression of Toll-like receptors on breast tumors: taking aToll on tumor microenvironment.” The immune system isintricately involved in the process of tumor progression andmetastasis and can play key roles in both tumor promotionand tumor suppression. TLRs are critical for innate andadaptive immunity and are expressed on inflammatory cellssurrounding the tumor. Recent studies have identified many TLRs expressed by tumor cells that may promote growthand immune evasion. This has led to the emergence of TLRsignaling as a potential target for the treatment of varioustumors.

One of the most common sites for the metastasis of breastcancer is to bone. In accordance with this, four papers focuson breast cancer metastasis to bone. B. Y. Reddy et al. putinto perspective the role of the microenvironment of thebone in breast cancer metastasis in “The microenvironmental e ff ect in the progression, metastasis, and dormancy of breast cancer: a model system within bone marrow.” The heteroge-neous composition of the bone microenvironment not only facilitates the growth of breast cancer cells but also supports

and protects the tumor cells. There is a bidirectional crosstalkbetween the cells comprising the bone microenvironmentand the metastatic breast cancer cells. While modulationof macrophage function can cause immune suppression,the release of inflammatory cytokines by adipocytes canstimulate tumor cell invasion, and the expression of SDF-1 by the myofibroblasts accelerates tumor cell growth. The contri-bution of mechanical stress in impacting tumor cell survival,elicitation of angiogenesis, and influencing drug delivery iselegantly summarized. This paper also discusses the roleof microenvironment-derived cytokines, chemokines, andmiRNA in inducing epithelial-mesenchymal changes andinfluencing cancer cell quiescence.

D. M. Sosnoski et al. present their findings on theinfluence of metastases on the levels of a variety of cytokinesand growth factors in the bone in their research article“Changes in cytokines of the bone microenvironment during breast cancer metastasis.” Using a xenograft model of breastcancer metastases to bone, they demonstrate that the pres-ence of the breast cancer cells in bone changes the normallevels of specific cytokines. Cytokines are important forbone remodeling, hematopoietic processes, and homeostaticbalance in the bone. Therefore, by altering cytokine levelsin the bone, metastatic breast cancer manipulates the bonemicroenvironment.

A complementary perspective on the dynamic dialoguebetween the stroma and the tumor cells, which impactsmetastasis of tumor cells to bone, is provided by E. Bevilac-qua et al. in “RKIP suppresses breast cancer metastasis tothe bone by regulating stroma-associated genes.” This focuseson the metastasis suppressor, Raf Kinase Inhibitory Protein(RKIP), and its ability to influence the tumor microenvi-ronment in the bone. RKIP inhibits breast cancer invasion,intravasation, and bone metastasis via the induction of miRNA let-7, resulting in suppression of the chromatin-remodeling factor HMGA2 and modulation of epithelial tomesenchymal plasticity. The use of a savvy, interdisciplinary approach involving expression arrays from breast cancerpatients yielded a deeper understanding of key regulatorsof genes that form the bone metastasis signature of cancercells, putting the spotlight on RKIP as a critical regulator of the tumor milieu and impacting the ability of tumor cells toestablish bone metastases.

The bone microenvironment is a fertile soil for metas-tasis with multiple regulatory molecules aff ecting growth.Accumulating evidence supports the notion that hedgehogsignaling plays a role in breast cancer metastasis to bone. In“The hedgehog pathway conditions the bone microenvironment  for osteolytic metastasis of breast cancer,” S. Das et al. discussour current understanding of how the hedgehog signalingpathway alters the bone microenvironment to promotemetastatic breast cancer growth. Hedgehog inhibitors may bea viable option for the treatment and/or prevention of breastcancer metastasis to bone.

Finally, J. W. Rostas and D. L. Dyess have providedthe surgeon’s perspective of current surgical managementof breast cancer in “Current operative management of breast cancer: an age of smaller resections and bigger cures.” Consider-ation of the tumor microenvironment is an emerging frontier

 

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in the treatment of breast cancer. The surgeon’s primary focus with breast-conserving surgery is obtaining tumor-free surgical margins, but there is a question as to whetherresidual stromal changes in the breast may aff ect localrecurrence. The authors emphasize that surgical interventionis currently the best hope for definitive cure of breast cancer;however, advances in the treatment of breast cancer as asystemic disease are needed to facilitate long-term cures.Patient-specific molecular diagnosis and the developmentof targeted chemotherapeutic agents are future hopes forimproved survival and will off er the surgeon an opportunity to be more focused and allow easier management of thedisease.

 Andra R. Frost Douglas R. Hurst 

Lalita A. ShevdeRajeev S. Samant