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The hematologic tumor microenvironment
New insights into early-stage bone colonization of disseminated cancer cells
Finally, solid cancers can metastasize into bone after hijacking the normal bone marrow microenvironment, as illustrated by the work of Dr Zhang and others. Upon col- onization of the bone marrow, cancer cells dysregulate bone formation and degradation cycles and stimulate the release of factors that promote tumor growth in a vicious cycle. Ell & Kang stated that: “TGFβ, insulin-like growth factor (IGF), and calcium are released from the bone matrix during lysis, enhancing tumor proliferation and survival. TGFβ signaling in tumor cells enhances expression of bone metastasis proteins including parathormone-related protein (PTHrP), the Notch ligand Jagged1, connective tissue growth factor (CTGF), IL-11, and matrix metalloproteinas- es. Calcium signaling through the calcium-sensing receptor leads to increased proliferation and survival. Osteoblasts also secrete a number of proteins that positively regulate tumor growth, including IL-6, secreted protein acidic and cysteine rich (SPARC) and periostin. SPARC induces cancer migration and homing through the αVβ5 integrin, whereas periostin and IL-6 promote tumor survival”.60
Whereas many molecules driving metastatic growth have been identified, there is an important lack of knowledge regarding mechanisms allowing cancer cell colonization and maintenance before expansion. The microenvironment of early-stage bone lesions appears to be primarily an osteogenic niche composed of alkaline phosphatase (ALP)+ collagen-I (ColI)+ cells which define a preosteolytic stage (osteoclasts are not yet predominant at this early stage). Cancer and osteogenic niche cells generate heterotypic adherent junctions formed by E-cadherin and N-cadherin. E-cadherin blockade can abolish spontaneous bone metas- tases in a manner dependent on mammalian target of rapamycin (mTOR) and p70.61 Moreover, cancer cells and niche cells are connected by gap junctions formed by con- nexin (Cx)43, which is induced in cancer cells after bone marrow colonization. Cx43 allows for calcium transfer to cancer cells to drive mTOR-dependent metastatic growth. This pathway can be inhibited by danusertib or a combina-
tion of everolimus and arsenic trioxide.62 This research illus- trates how solid tumors may hijack normal bone marrow niches to drive metastatic growth.
Summary
Increasingly, the tumor microenvironment is the focus of studies addressing survival, growth and chemoresistance of solid tumors and hematologic malignancies since it plays critical roles in disease initiation, maintenance and relapse. A key challenge is the dual role of the microenvironment in regulating normal and malignant hematopoiesis, since inhibiting the development and maintenance of malignan- cies must be followed by the reestablishment of normal tis- sue function. Therapies targeting the tumor microenviron- ment (which not only comprises the immune system, but also the stromal and endothelial cells that interact with the malignant cells and the immune cells) must simultaneously eliminate chemoresistant cells and preserve/reestablish nor- mal hematopoiesis. Multidisciplinary meetings uniting basic and clinical researchers concerned about the tumor microenvironment have proven a unique opportunity for cross-fertilization of scientific knowledge, ideas and approaches to identify key vulnerabilities of the malignant niches.
Acknowledgments
The authors apologize for the omission of relevant literature due to the focus of this review. The support of the European School of Hematology (ESH), Celgene, Janssen Oncology, Fluidigm and Cancer Research UK was critical for the organization of the Workshop on which this article is based. This work was supported by Bologna AIL and AIRC Associazione Italiana per la Ricerca sul Cancro with funding to DF, and core support grants from the Wellcome Trust and the Medical Research Council to the Cambridge Stem Cell Institute, National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 Research (ERC-2014-CoG-64765) and a Programme Foundation Award from Cancer Research UK to SM-F.
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