Role Of Tumor Microenvironment Research Articles

Matrix Metalloproteinases' Role in Tumor Microenvironment.

Cancer cells evolve in the tumor microenvironment (TME) by the acquisition of characteristics that allow them to initiate their passage through a series of events that constitute the metastatic cascade. For this purpose, tumor cells maintain a crosstalk with TME non-neoplastic cells transforming them into their allies. "Corrupted" cells such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs) as well as neoplastic cells express and secrete matrix metalloproteinases (MMPs). Moreover, TME metabolic conditions such as hypoxia and acidification induce MMPs' synthesis in both cancer and stromal cells. MMPs' participation in TME consists in promoting events, for example, epithelial-mesenchymal transition (EMT), apoptosis resistance, angiogenesis, and lymphangiogenesis. MMPs also facilitate tumor cell migration through the basement membrane (BM) and extracellular matrix (ECM). The aim of the present chapter is to discuss MMPs' contribution to the evolution of cancer cells, their cellular origin, and their influence in the main processes that take place in the TME.

Research progress on the role of tumor microenvironment in tumor metastasis

Research progress on the role of tumor microenvironment in tumor metastasis

Eosinophils in the Tumor Microenvironment.

Eosinophils are rare blood-circulating and tissue-infiltrating immune cells studied for decades in the context of allergic diseases and parasitic infections. Eosinophils can secrete a wide array of soluble mediators and effector molecules, with potential immunoregulatory activities in the tumor microenvironment (TME). These findings imply that these cells may play a role in cancer immunity. Despite these cells were known to infiltrate tumors since many years ago, their role in TME is gaining attention only recently. In this chapter, we will review the main biological functions of eosinophils that can be relevant within the TME. We will discuss how these cells may undergo phenotypic changes acquiring pro- or antitumoricidal properties according to the surrounding stimuli. Moreover, we will analyze canonical (i.e., degranulation) and unconventional mechanisms (i.e., DNA traps, exosome secretion) employed by eosinophils in inflammatory contexts, which can be relevant for tumor immune responses. Finally, we will review the available preclinical models that could be employed for the study of the role in vivo of eosinophils in cancer.

277P - Correlation of clinical and pathological features with the tumour microenvironment in DCIS: An institutional experience

BackgroundThe predictors of recurrence in ER- DCIS and the role of tumor microenvironment (TME) is unclear. Correlation of clinico-pathologic features of ER- DCIS with molecular markers and PD-L1 expression has not been done. Therefore, we under took this retrospective study comparing the clinical outcomes between ER+ and ER- DCIS and correlated this with the expression of PD-L1 in the tumor cells and the Tumor infiltrating lymphocytes. We hypothesize that increased expression of PD-L1 in ER- DCIS and TILs predict recurrence. The aim of this study was to identify biomarkers in ER- DCIS associated with increased risk of recurrence or progression to metastatic disease. Methods50 patients with ER+ and ER- DCIS were identified retrospectively. Clinico-pathologic data was correlated with survival outcomes and local or distant recurrence. Information collected was the size, margin status, nuclear grade, ki-67 expression, architectural pattern, necrosis, and molecular phenotype. 25 cases of ER- DCIS are presented in the abstract. The rest will be presented at the meeting. ER+ and ER- DCIS will be stained for PD-L1, and lymphocyte markers CD3, CD4, CD8, FoxP3, and CD20 for the TILs in ER+ and ER- DCIS. The clinical, radiological and Immuno-pathologic features of ER+ DCIS will be compared with ER negative DCIS. Results3/25 (12%) had disease recurrence. Two (67%) had recurrence with metastatic triple negative breast cancer with brain, hepatic and osseous metastasis within 5 years. High grade was associated with the development of systemic disease. 1/3 (33%) had recurrence as ER negative DCIS. 2/3 (67%) had recurrence as ER+ tumor. The rate of recurrence and distant metastasis was seen to be higher in high grade ER negative DCIS. ConclusionsER- DCIS has an aggressive phenotype and a distinct biology. It is more likely to present as loco-regional or metastatic disease. Identification of genomic biomarkers, PD-L1 analysis in the tumor and the TILs is currently being undertaken. The molecular drivers and immunologic markers of recurrence in ER negative DCIS continue to be an active area of exploration. Further characterization of ER- DCIS immune microenvironment may identify useful targets for immune-based therapy and breast cancer prevention. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

The prognostic value of systemic immune-inflammation index (SII) in patients after radical operation for carcinoma of stomach in gastric cancer.

The inflammatory reaction, which plays a key role in tumor microenvironment, is associated with the tumor development, progression and metastasis. We aim to estimate the potential prognostic value of systemic immune-inflammation index (SII) in patients after radical operation for carcinoma of stomach in gastric cancer. One hundred and eighty-two patients with gastric cancer who underwent radical operation for carcinoma of stomach from January 2009 to December 2012 were enrolled and divided into a low SII group (<600×109 cells/L) and a high SII group (SII ≥600×109 cells/L) based on the optimal cutoff value of SII. The clinicopathological features were analyzed and compared between the two groups of patients. We analyzed the disease-free survival (DFS) and the overall survival (OS) by Kaplan Meier survival curve and log-rank test. The prognostic factors were used to evaluate by univariate analysis, and the independent prognostic factors were assessed by using multivariate Cox proportional hazards regression model. The median DFS and OS of all patients were 18.67 and 22.83 months, respectively. According to the univariate and multivariate analysis, the optimal cutoff value of SII had prognostic significance on DFS and OS. The median DFS and OS in low SII group were longer than those in high SII group (21.43 vs. 17.57 months, 28.03 vs. 18.30 months, respectively). The radical resection, type of surgery, metastatic lymph nodes ratio (MLNR), lymphocyte, SII, carcinoembryonic antigen (CEA) and Borrmann classification were the independent prognostic factors in gastric carcinoma. At the same time, the patients with MLNR in low SII group had longer DFS and OS than those with MLNR in high SII group, especially in patients with high MLNR. SII may serve as a convenient, low-cost and noninvasive prognostic marker for patients after radical operation for carcinoma of stomach in gastric cancer.

Glioblastoma extracellular vesicles induce the tumour-promoting transformation of neural stem cells.

Recurrent glioblastomas are frequently found near subventricular zone (SVZ) areas of the brain where neural stem cells (NSCs) reside, and glioblastoma-derived extracellular vesicles (EVs) are reported to play important roles in tumour micro-environment, but the details are not clear. Here, we investigated the possibility that NSCs are involved in glioblastoma relapse mediated by glioblastoma-derived EVs. We studied changes to NSCs by adding glioblastoma-derived EVs into a culture system of NSCs, and found that NSCs differentiated into a type of tumour-promoting cell. These transformed cells had distinguished proliferation activity, a high migration rate, and clone-forming ability revealed by CCK-8, wound healing and soft agar clone formation assays, respectively. In vivo assays indicated that these cells could accelerate tumour formation by Ln229 cells in nude mice. Moreover, to explore the mechanisms underlying NSC transformation, single cell transcriptome sequencing was performed; our results suggest that several key genes such as S100B, CXCL14, EFEMP1, SCRG1, GLIPR1, HMGA1 and CD44 and dysregulated signalling may be important for the transformation of NSCs. It is also indicated that NSCs may be involved in glioblastoma recurrence through EV release by glioblastoma in this work. This could help to illuminate the mechanism of glioblastoma relapse, which occurs in a brief period after surgical excision, and contribute to finding new ways to treat this disease.

Vasculogenic Mimicry: Become an Endothelial Cell "But Not So Much".

Blood vessels supply all body tissues with nutrients and oxygen, take away waste products and allow the arrival of immune cells and other cells (pericytes, smooth muscle cells) that form part of these vessels around the principal endothelial cells. Vasculogenic mimicry (VM) is a tumor blood supply system that takes place independently of angiogenesis or endothelial cells, and is associated with poor survival in cancer patients. Aberrant expression of VE-cadherin has been strongly associated with VM. Even more, VE-cadherin has constitutively high phosphorylation levels on the residue of Y658 in human malignant melanoma cells. In this review we focus on non-endothelial VE-cadherin and its post-translational modifications as a crucial component in the development of tumor VM, highlighting the signaling pathways that lead to their pseudo-endothelial and stem-like phenotype and the role of tumor microenvironment. We discuss the importance of the tumor microenvironment in VM acquisition, and describe the most recent therapeutic targets that have been proposed for the repression of VM.

Mechanisms and Functional Significance of Human Tumor-infiltrating Myeloid Cells

Myeloid cells as the major components of tumor-infiltrating leukocytes play critical roles in anti-tumor immunity. However, emerging evidences have revealed that soluble factors produced by tumor/stromal cells skew myeloid cells toward a tumor-promoting phenotype. Tumor-infiltrating myeloid cells (TIMs) including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs) are considered as the key mediators of tumor microenvironment (TME). TIMs have been shown to play important roles in various aspects of cancer biology and their presence is often linked to altered patient prognosis and survival. Regarding their critical role in TME, TIMs have been proposed as relevant targets of therapeutic strategies aimed at expanding immunostimulatory myeloid cell populations and depleting or modulating immunosuppressive ones. In this review, we briefly describe TIMs subsets and discuss the mechanisms by which TIMs induce immunosuppression, angiogenesis, and metastasis.

Kinins in Glioblastoma Microenvironment.

Tumour progression involves interactions among various cancer cell clones, including the cancer stem cell subpopulation and exogenous cellular components, termed cancer stromal cells. The latter include a plethora of tumour infiltrating immunocompetent cells, among which are also immuno-modulatory mesenchymal stem cells, which by vigorous migration to growing tumours and susequent transdifferentiation into various types of tumour-residing stromal cells, may either inhibit or support tumour progression. In the light of the scarce therapeutic options existing for the most malignant brain tumour glioblastoma, mesenchymal stem cells may represent a promising novel tool for cell therapy, e.g. drug delivery vectors. Here, we review the increasing number of reports on mutual interactions between mesenchymal stem cells and glioblastoma cells in their microenvironment. We particularly point out two novel aspects: the different responses of cancer cells to their microenvironmental cues, and to the signalling by kinin receptors that complement the immuno-modulating cytokine-signalling networks. Inflammatory glioblastoma microenvironment is characterised by increasing expression of kinin receptors during progressive glioma malignancy, thus making kinin signalling and kinins themselves rather important in this context. In general, their role in tumour microenvironment has not been explored so far. In addition, kinins also regulate blood brain barrier-related drug transfer as well as brain tumour angiogenesis. These studies support the on-going research on kinin antagonists as candidates in the development of anti-invasive agents for adjuvant glioblastoma therapy.

Abstract 1193: S100A proteins play immune regulatory roles in tumor microenvironment

Abstract S100A proteins are Ca2+ binding multifunctional molecule in different cellular compartments. Dysregulated expression of S100A is often observed in many types of human cancers, and is assoiciated with cancer pathogenesis. Inside a cell, S100A proteins respond to various stimuli, and some typical intracellular functions such as cytoskeleton control and motility have been extensively studied. Extracellular functions of S100A proteins have recently emerged, and they bind innate immune receptors such as TLR4 and RAGE. Nevertheless, the mode of S100A secretion has been obscure. We designed a secretion system to induce spontaneous S100A release from the cell, and examined their roles towards tumor microenvironment. We found S100A proteins are included in exosomes, and the stability of S100A contributes to their extracellular functions. Using a syngeneic tumor model, we investigated some S100A proteins show immune regulatory functions on tumor-associated macrophages. These results suggest that S100A secretion affects tumor immune environment. Note: This abstract was not presented at the meeting. Citation Format: Nobuyuki Tanaka, Natsumi Kodake, Naoko Ogama. S100A proteins play immune regulatory roles in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1193.

Prognostic Impact of Adenosine Receptor 2 (A2aR) and Programmed Cell Death Ligand 1 (PD-L1) Expression in Colorectal Cancer.

Background Programmed cell death ligand 1 (PD-L1) is a key inhibitor to the immune response by binding to the specific receptor PD-1. Adenosine receptor 2 (A2aR) can play an immunosuppressive role in tumor microenvironment by binding to its ligand adenosine (ADO). However, the expression of these two markers has been rarely studied in colorectal cancer simultaneously. Materials and Methods We, respectively, collected tumor and adjacent nontumor tissue specimens of 204 patients with colorectal cancer. The expressions of PD-L1 and A2aR were detected by immunohistochemistry. The association among their expressions with clinicopathological characteristics and prognostic parameters were analyzed as well. Results The expressions of PD-L1 and A2aR in tumor tissues were both higher than those in matched adjacent nontumor tissues. PD-L1 expression was significantly correlated with lymph node metastasis and tumor TNM stage. A2aR expression was significantly correlated with tumor size, depth of tumor invasion, and TNM stage. Univariate analysis showed that the high expressions of PD-L1 and A2aR were inversely correlated with the overall survival, respectively. Multivariate analysis further confirmed that both of them were independent prognostic markers for patients. Conclusion The results of this study suggested that the high expressions of PD-L1 and A2aR were associated with a poor prognosis of colorectal cancer. Coinhibition of these two proteins may be a new breakthrough in the treatment of this disease.

Chemoresistance in mesenchymal lung cancer cells is correlated to high regulatory T cell presence in the tumor microenvironment.

Most deaths due to lung cancer are a result of metastatic progression. One major problem in treating patients with lung cancer is either the inherent or acquired resistance to chemotherapy. Role of tumor microenvironment in disease progression and resistance to chemotherapy is being increasingly appreciated and reported for various cancers. Hence, the objective of the current study was to define the lung cancer tumor microenvironment. Biopsy tissue specimens and blood samples were collected from stage I-IV lung patients (n = 53). Epithelial and mesenchymal A549 cells were used to test chemosensitivity. CD3+ T cells are the major tumor-infiltrating T lymphocyte subsets in patients with lung cancer, which were independent of disease stage. Functional analysis indicated high expression of the CD4+ helper T cells and low expression of the CD8+ cytotoxic T cells in lung cancer tissue compared to tumor adjacent normal tissue. Within the CD4+ T cell subset, there seems to be significant increase in the regulator T cells (Tregs) which are known to help the tumor in evading the immune system. CDH1 (encoding the epithelial cell marker E-cadherin) and IL2RA (encoding the Treg marker CD25) expression in patients with stage IV lung cancer that were resistant to cisplatin treatment showed an inverse correlation between IL2RA (high) and CDH1 (low) expression. Our results indicate that lung tumor is enriched in Tregs which might potentially explain how lung tumors evade the immune system. © 2019 IUBMB Life, 2019.

Obesity-Altered Adipose Stem Cells Promote ER+ Breast Cancer Metastasis through Estrogen Independent Pathways

Adipose stem cells (ASCs) play an essential role in tumor microenvironments. These cells are altered by obesity (obASCs) and previous studies have shown that obASCs secrete higher levels of leptin. Increased leptin, which upregulates estrogen receptor alpha (ERα) and aromatase, enhances estrogen bioavailability and signaling in estrogen receptor positive (ER+) breast cancer (BC) tumor growth and metastasis. In this study, we evaluate the effect of obASCs on ER+BC outside of the ERα signaling axis using breast cancer models with constitutively active ERα resulting from clinically relevant mutations (Y537S and D538G). We found that while obASCs promote tumor growth and proliferation, it occurs mostly through abrogated estrogen signaling when BC has constitutive ER activity. However, obASCs have a similar promotion of metastasis irrespective of ER status, demonstrating that obASC promotion of metastasis may not be completely estrogen dependent. We found that obASCs upregulate two genes in both ER wild type (WT) and ER mutant (MUT) BC: SERPINE1 and ABCB1. This study demonstrates that obASCs promote metastasis in ER WT and MUT xenografts and an ER MUT patient derived xenograft (PDX) model. However, obASCs promote tumor growth only in ER WT xenografts.

Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy.

Chemokines are small secreted proteins that orchestrate migration and positioning of immune cells within the tissues. Chemokines are essential for the function of the immune system. Accumulating evidence suggest that chemokines play important roles in tumor microenvironment. In this review we discuss an association of chemokine expression and activity within the tumor microenvironment with cancer outcome. We summarize regulation of immune cell recruitment into the tumor by chemokine-chemokine receptor interactions and describe evidence implicating chemokines in promotion of the “inflamed” immune-cell enriched tumor microenvironment. We review both tumor-promoting function of chemokines, such as regulation of tumor metastasis, and beneficial chemokine roles, including stimulation of anti-tumor immunity and response to immunotherapy. Finally, we discuss the therapeutic strategies target tumor-promoting chemokines or induce/deliver beneficial chemokines within the tumor focusing on pre-clinical studies and clinical trials going forward. The goal of this review is to provide insight into comprehensive role of chemokines and their receptors in tumor pathobiology and treatment.

Role of Microenvironment on the Fate of Disseminating Cancer Stem Cells

Disseminating Cancer Stem Cells (CSCs) initiate growth in specific niches of the host tissues, the cellular and molecular components of which sustain signaling pathways that support their survival, self-renewal dormancy and reactivation. In the metastatic niche, tumor cells may enter in a dormant state to survive and, consequently, the metastasis can remain latent for years. Despite the clinical importance of metastatic latency, little is known about what induces CSCs to enter a dormant state and what allows them to remain viable for years in this state. CSCs exhibit genetic, epigenetic and cellular adaptations that confer resistance to classical therapeutic approaches. The identification of potential CSC targets is complicated by the fact that CSCs may arise as a consequence of their relationship with the local microenvironment into the metastatic niches. Indeed, microenvironment modulates the capability of CSCs to evade the innate immune response and survive. Some new therapeutic options that include drugs targeting microenvironment components are achieving encouraging results in reducing the number of CSCs in tumors and/or overcoming their resistance in preclinical studies. This review will focus on specific CSC features with an emphasis on the role of tumor microenvironment in supporting metastatic dissemination of CSCs. In addition, it sheds light on potential microenvironment-targeted therapies aimed to counteract seeding and survival of CSCs in the metastatic niche.

Abstract B135: Novel immunotherapeutic strategy based on the immunopathologic properties of cancer stem cells

Abstract Cancer stem-like cells (CSCs) are small subpopulation of cancer cells that contribute to cancer initiation and progression. These cells have a huge impact in the field of cancer therapy since they are resistant to standard chemoradiotherapy and responsible for disease recurrence. We have studied immunopathologic properties of CSCs derived from colon, breast, and gynecologic cancers to develop a novel CSC-targeted immunotherapy. #1 CSC-specific antigens: CSCs express several germ cell-specific genes. Remarkably, some of them were involved in tumor initiation capacity of CSCs and highly immunogenic since specific cytotoxic T-cells (CTLs) were efficiently induced from peripheral blood lymphocytes. The CTLs exerted specific cytotoxicity against CSCs. Adoptive transfer of the CSC-specific CTLs efficiently protected tumor growth in mouse models. #2 Fibroblastic niche of CSCs: Cancer-associated fibroblasts (CAFs) have important roles in tumor microenvironment. CSCs recruited fibroblasts, which enhanced tumor initiation capacity and immune resistance of CSCs. Gene expression analysis revealed that fibroblast growth factor 4 (FGF4) and FGFR2, a receptor for FGF4 were involved in the fibroblastic niche of CSCs. #3 Innate PD-L1 expression of CSCs: Some CSCs constitutively expressed PD-L1 on the cell surface through activation of PI3K/AKT signaling. Based on these unique properties of CSCs, we propose immunotherapeutic and immunoprophylactic strategy targeting CSCs. Citation Format: Toshihiko Torigoe, Yoshihiko Hirohashi. Novel immunotherapeutic strategy based on the immunopathologic properties of cancer stem cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B135.

Screening Five Qi-Tonifying Herbs on M2 Phenotype Macrophages.

Tumor-associated macrophages (TAMs) with M2 phenotype play an essential role in tumor microenvironment (TME) during the progression and development of numerous cancers and associated with poor prognosis. Thus, regulation of TAMs polarization emerged as a new strategy for tumor immune therapy. According to Traditional Chinese Medicine (TCM) theory, herbs with Qi-tonifying character are involved in improving the defense capacity of immune system. In this study, we screened extracts and ingredients from five Qi-tonifying herbs exhibiting an inhibitory effect on M2 polarization of murine macrophages RAW264.7 induced by IL-4 and IL-13. Among these candidates, total flavonoids from Glycyrrhiza Radix et Rhizoma (TFRG) and ethanol extract of Ginseng Radix et Rhizoma significantly inhibited the expression of Arginase-1 (Arg-1) (above 90% at 100μg/mL), one of the phenotype markers of M2 macrophages. The inhibition of total saponins of Ginseng Radix et Rhizoma, ethanol extract of Cordyceps, ethanol extract of Acanthopanacis senticosi Radix et Rhizoma Seu caulis, and ethanol extract of Astragali Radix reached above 50% at 100μg/mL. The inhibition of ingredients including glabridin, isoliquiritin apioside, lysionotin, cordycepin, astragaloside IV, and calycosin reached above 50% at 50μM. Then, we investigated the molecular mechanisms of TFRG. TFRG abolished the migration of murine breast cancer 4T1 stimulated by the conditioned medium from M2 macrophages (M2-CM). In addition to Arg-1, TFRG also antagonized the IL-4/13-mediated mRNA upregulation of the M2 markers including found in inflammatory zone 1 (FIZZ1), chitinase-3-like protein 3 (YM1), and mannose receptor (CD206) and upregulated the expression of inducible nitric oxide synthase (iNOS), one of the M1 markers. The further exploration showed that TFRG decreased the phosphorylation of STAT6 and increased the expression of miR-155. Our study provides a series of potential immune regulating natural products from five Qi-tonifying herbs on M2 phenotype. For instance, TFRG suppressed M2 polarization of macrophages partly by inactivating STAT6 pathway and enhanced the level of miR-155 to regulate the expressions of M1 and M2 markers.

Current Progresses of Exosomes as Cancer Diagnostic and Prognostic Biomarkers.

Cancer related exosomes are nano-size membrane vesicles that play important roles in tumor microenvironment. Emerging evidence indicates that exosomes can load unique cargoes, including proteins and nucleic acids that reflect the condition of tumor. Therefore, exosomes are being used as diagnostic and prognostic biomarkers for various cancers. In this review, we describe the current progresses of cancer related exosomes, including their biogenesis, molecular contents, biological functions, sources where they are derived from, and methods for their detection. We will also discuss the current exosomal biomarkers and the utilization of them for early diagnosis and prognostics in cancer.

Unveiling the role of tumor micro-environment

Unveiling the role of tumor micro-environment

Up-regulation of SPINT2/HAI-2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion.

The role of tumour microenvironment in neoplasm initiation and malignant evolution has been increasingly recognized. However, the bone marrow mesenchymal stromal cell (BMMSC) contribution to disease progression remains poorly explored. We previously reported that the expression of serine protease inhibitor kunitz‐type2 (SPINT2/HAI‐2), an inhibitor of hepatocyte growth factor (HGF) activation, is significantly lower in BMMSC from myelodysplastic syndromes (MDS) patients compared to healthy donors (HD). Thus, to investigate whether this loss of expression was due to SPINT2/HAI‐2 methylation, BMMSC from MDS and de novo acute myeloid leukaemia (de novo AML) patients were treated with 5‐Azacitidine (Aza), a DNA methyltransferase inhibitor. In MDS‐ and de novo AML‐BMMSC, Aza treatment resulted in a pronounced SPINT2/HAI‐2 levels up‐regulation. Moreover, Aza treatment of HD‐BMMSC did not improve SPINT2/HAI‐2 levels. To understand the role of SPINT2/HAI‐2 down‐regulation in BMMSC physiology, SPINT2/HAI‐2 expression was inhibited by lentivirus. SPINT2 underexpression resulted in an increased production of HGF by HS‐5 stromal cells and improved survival of CD34+ de novo AML cells. We also observed an increased adhesion of de novo AML hematopoietic cells to SPINT2/HAI‐2 silenced cells. Interestingly, BMMSC isolated from MDS and de novo AML patients had increased expression of the integrins CD49b, CD49d, and CD49e. Thus, SPINT2/HAI‐2 may contribute to functional and morphological abnormalities of the microenvironment niche and to stem/progenitor cancer cell progression. Hence, down‐regulation in SPINT2/HAI‐2 gene expression, due to methylation in MDS‐BMMSC and de novo AML‐BMMSC, provides novel insights into the pathogenic role of the leukemic bone marrow microenvironment.