Migratory neighbors and distant invaders: tumor-associated niche cells

Abstract

The cancer environment is comprised of tumor cells as well as a wide network of stromal and vascular cells participating in the cellular and molecular events necessary for invasion and metastasis. Tumor secretory factors can activate the migration of host cells, both near to and far from the primary tumor site, as well as promote the exodus of cells to distant tissues. Thus, the migration of stromal cells and tumor cells among specialized microenvironments takes place throughout tumor and metastatic progression, providing evidence for the systemic nature of a malignancy. Investigations of the tumor-stromal and stromal-stromal cross-talk involved in cellular migration in cancer may lead to the design of novel therapeutic strategies.Understanding the complex biological networks at play in metastasis requires a precise detailing of the molecular and cellular pathways involved in local and systemic migration. The long prevailing model of invasion and metastasis has focused on the adhesive and migratory capabilities that are intrinsic to tumor cells (Hanahan and Weinberg 2000). Meanwhile, we are becoming increasingly aware that tumors are composed of genetically altered malignant cells along with a heterogeneous population of stromal cells, whose dynamic interactions can profoundly enhance tumor progression and metastasis. Through the production of chemokines, growth factors, and matrix-degrading enzymes (Table 1), supportive cells-including fibroblasts, immune cells, and bone marrow (BM)-derived stem and progenitor cells-support blood vessel formation, break down basement membrane barriers, and attract tumor cells to distant sites. Tumor cells are constantly giving instructions, not only by direct cell-cell interactions, but also by secreted factors that "activate" normal host cells at both proximal and distal sites to migrate, eventually developing permissive niches that, in return, promote tumor cell survival and proliferation. The focus of this review is on the cellular constituents of the primary and metastatic tumor microenvironments, with emphasis on their migratory pathways. We hope to convey that the tumor and host cell interaction is truly reciprocal; while host cells may support tumor cells, tumor cells in turn modulate the microenvironments within which they reside. Furthermore, we highlight that cancer is a systemic disease, encompassing collective cell movements of tumor and stromal cells that are a prerequisite for tumor cell invasion and metastasis. Intrinsic tumor cell migratory capabilitiesInherent to the metastatic process is the capability of tumor cells to migrate through connective tissue barriers comprising cell-cell adherent junctions, basement membranes, and interstitial tissue stroma. This intrinsic migratory behavior is highly dependent on the interplay between adhesive and proteolytic activities. Tumor cell down-regulation of proteins mediating cell-cell interactions, such as cadherins, leads to changes in cell signaling, actin-based cytoskeletal structure, and eventual dissociation from n...

Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis

“…It is well known that primary tumors secrete signals (altered proteins) that aff ect, in a selective way, specifi c stromal tissue favouring CSCs niche (Chiang and Massagué 2008;Witz 2008). Once CSCs colonize these conditioned stromas, they may remain for long periods of time in a dormant state before activating and producing metastases (Kaplan et al 2006;Wels et al 2008). This may explain the recurrence after apparently curative surgery in many cancers.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…The N1 cells are characterized by cytotoxic activity towards tumor cells and an immunostimulatory profile (i.e., TNFα high , CCL3 high , ICAM-1 high , Arginase low ), whereas N2 neutrophils are characterized by upregulation of the chemokines CCL2, 3,4,8,12, and 17, and CXCL1, 2, 8 and 16 [10]. N1 cells produce more superoxide and hydrogen peroxide and express higher levels of Fas, TNFα, CCL3 and ICAM-1, but lower levels of Arginase, CCL2, CCL5, VEGF, CXCR4 and MMP-9 than N2 cells [10].…”

“…Within the tumor microenvironment, there is a continuous crosstalk between tumor cells, stromal cells and cells of the immune system [1][2][3]. Tumor cells secrete a wide range of cytokines and chemokines that not only attract and affect macrophages, neutrophils, dendritic cells, NK-, B-and Tcells, but also regulate other stromal cells, endothelial cells and the tumor cells themselves.…”

“…Cells of the innate and adaptive immune system in turn mutually affect the activation status of other immune cells and attract more leukocytes into the tumor cell mass. Surprisingly, non-malignant immune cells can make up 90 % of the total tumor mass [2][3][4][5]. However, it is the integration of all signals encountered within the tumor microenvironment that affects the composition and activation of the various immune cells within the tumor cell mass and ultimately leads to either antitumor or pro-tumor activities.…”

Roles of TGFβ in metastasis

“…Indeed, recent work has identified the key mediators of extravasation, microenvironment remodeling, homing, invasion, migration, and survival [3]. Interestingly, the TGFb pathway has been implicated in many of these metastatic processes and has been shown to dramatically impact the ability of tumor cells to spread throughout the body [5][6][7][8].…”