Cancer Microenvironment最新文献

A wide spectrum of both normal and diseased cell types shed extracellular vesicles that facilitate intercellular communication without direct cell-to-cell contact. Microparticles (MPs) are a subtype of extracellular vesicles that participate in multiple biological processes. They carry abundant bioactive molecules including different forms of nucleic acids and proteins that can markedly modulate cellular behavior. MPs are involved in several hallmarks of cancer such as drug resistance, thrombosis, immune evasion, angiogenesis, tumor invasion and metastasis. Such MPs originate from either cancer or other host cells. As MPs are secreted and can be detected in various body fluids, they can be used as potential diagnostic and prognostic biomarkers as well as vehicles for delivery of cytotoxic drugs. This review summarizes accumulating evidence on the biological properties of MPs in cancer, with reference to their potential usage in clinical settings.

Identification of gene expression mechanisms began with works on embryonic induction. The same mechanism of cell-cell interactions also contributes to the process of oncogenesis. Damage to epithelial cells' genetic apparatus turns them into precancerous stem cells that are not yet capable of tumor growth. They can be transformed into cancer stem cells and undergo further progression as a result of epigenetic effects of apocrine secretion by surrounding activated stromal cells (mostly myofibroblasts). These factors may activate the damaged genetic information. On the contrary, the level of malignancy can be decreased by adding culture medium from non-activated stromal cells. One must not exclude the possibility that in a number of cases genetically altered bone marrow may migrate to damaged or inflamed tissues and become there a source of stromal cells, as well as of parenchymal stem cells in a damaged organ, where they may give rise to changed epithelial (precancerous) stem cells or to activated stromal cells, thus leading to malignant tumor growth. Cancer treatment should also affect activated stromal cells. It may prevent emergence and progression of cancerous stem cells.

To study the mechanism of interaction of tumor cells with bone marrow cells continuous wave electron paramagnetic resonance (EPR) experiments at 9 GHz including a spin trapping of superoxide were carried out. The common features of the EPR spectra in healthy and tumor affected tissues of donors and rats as well as their difference are presented and discussed. It is proposed that labile iron pool plays a significant role in mechanisms of tumor invasion. We hope that the observed EPR features could be used to study the mechanisms of invasion and progression of tumor in different organs.

Approximately 1 in 14 men and women during their lifetime will be diagnosed with lung cancer, which is the leading cause of cancer-related mortality in the world. As of January 1, 2008, there were about 373,500 men and women living with lung cancer in the United States. Fewer than 60,000 of these are estimated to be alive by January 2013, reflecting a poor overall 5-year relative survival rate of under 16 %. With metastatic cancer, the overall 5-year survival is meager 4 %. On the other hand, the overall five-year survival is over 50 % when the cancer is still in the localized stage. However, unfortunately, more than half of cases of lung cancer are diagnosed at an advanced stage Howlader et al. (2010). Cancer metastasis, the single most critical prognostic factor, is still poorly understood and a highly complex phenomenon. The most common sites of lung cancer metastasis are the lymph nodes, liver, adrenals, brain and bones. The gastrointestinal (GI) tract is an exceptionally rare site of metastasis; with only a handful of cases reported in the literature Centeno et al. (Lung Cancer, 18: 101-105, 1997); Hirasaki et al. (World J Gastroenterol, 14: 5481-5483, 2008); Carr and Boulos (Br J Surg, 83: 647, 1996); Otera et al. (Eur Respir Rev, 19: 248-252, 2010); Antler et al. (Cancer, 49: 170-172, 1982); Fujiwara et al. (Gen Thorac Cardiovasc Surg, 59: 748-752, 2011); Stinchcombe et al. (J Clin Oncol, 24: 4939-4940, 2006); John et al. (J Postgrad Med, 48: 199-200, 2002); Carroll and Rajesh (Eur J Cardiothorac Surg, 19: 719-720, 2001); Brown et al. (Dis Colon Rectum, 23: 343-345, 1980). We report three cases of non-small cell (squamous cell) lung cancer with GI tract metastasis-two in the colon and one in the jejunum. Then we present a review of literature exploring various theories of metastasis, as an attempt to understand the reason of preferential tumor metastasis.

Chemokine receptors mediate cancer progression and metastasis. We have previously examined chemokine receptor CCR9 expression in pancreatic cancer. Here, our objective was to evaluate pancreatic stellate cells (PSCs) as a source of CCL25, the CCR9 ligand, and as an activator of CCL25-CCR9 signaling in pancreatic cancer cells. CCL25 and CCR9 expression levels in human pancreatic cancer tissues and normal human pancreas were assessed by immunohistochemsitry. In vitro secretion of CCL25 in PSCs and PANC-1 cells was verified by enzyme-linked immunosorbent assay. Pancreatic cancer cell invasion was measured using a modified Boyden chamber assay with CCL25, PSC secreted proteins, and PANC-1 secreted proteins as the chemoattractant. There was immunostaining for CCR9 expression in human pancreatic tumor tissues, but not in normal pancreatic tissue. CCL25 expression was absent in the normal pancreatic tissue sample, but was observed in cancer cells and in the stromal cells surrounding the tumor. In vitro, both PANC-1 cells and PSCs secreted CCL25. In an invasion assay, exposure to CCL25, PSC- and PANC-1-conditioned media significantly increased the invasiveness of PANC-1 cells. Inclusion of a CCR9-neutralizing antibody in the invasion assay blocked the increase in invading cells elicited by the chemoattractants. Our studies show that pancreatic cancer invasiveness is enhanced by autocrine and paracrine stimulation of CCR9. PSCs in the tumor microenvironment appear to contribute to paracrine activation of CCR9. Investigations into CCR9 as a potential therapeutic target in pancreatic cancer must consider cancer cell autocrine signaling and also paracrine signaling from interactions in the tumor microenvironment.

Prostate cancer (PC) bone metastases show weak responses to conventional therapies. Bone matrix is rich in growth factors, with insulin-like growth factor-1 (IGF-1) being one of the most abundant. IGF-1 acts as a survival factor for tumor cells and we speculate that bone-derived IGF-1 counteracts effects of therapies aimed to target bone metastases and, consequently, that therapeutic effects could be enhanced if given in combination with IGF-1 receptor (IGF-1R) inhibitors. Simvastatin inhibits the mevalonate pathway and has been found to induce apoptosis of PC cells. The aims of this study were to confirm stimulating effects of bone-derived IGF-1 on PC cells and to test if IGF-1R inhibition enhances growth inhibitory effects of simvastatin on PC cells in a bone microenvironment. The PC-3 and 22Rv1 tumor cell lines showed significantly induced cell growth when co-cultured with neonatal mouse calvarial bones. The tumor cell IGF-1R was activated by calvariae-conditioned media and neutralization of bone-derived IGF-1 abolished the calvarium-induced PC-3 cell growth. Treatment of PC-3 and 22Rv1 cells with simvastatin, or the IGF-1R inhibitor NVP-AEW541, reduced tumor cell numbers and viability, and induced apoptosis. Combined simvastatin and NVP-AEW541 treatment resulted in enhanced growth inhibitory effects compared to either drug given alone. Effects of simvastatin involved down-regulation of IGF-1R in PC-3 and of constitutively active androgen receptor variants in 22Rv1 cells. In conclusion, we suggest that IGF-1 inhibition may be a way to strengthen effects of apoptosis-inducing therapies on PC bone metastases; a possibility that needs to be further tested in pre-clinical models.

U19/EAF2 is regulated by androgens in the prostate and capable of regulating transcriptional elongation of RNA Pol II via interaction with the ELL family proteins. Inactivation of U19/EAF2 induces tumorigenesis in multiple organs; however the mechanism of U19/EAF2 tumor suppression remains unclear. To elucidate potential mechanisms of U19/EAF2 action, we performed cDNA microarray analysis and identified 164 mRNA transcripts regulated by U19/EAF2 in the mouse ventral prostate. Bioinformatics analysis indicated that U19/EAF2 knockout activates the RAS-BRAF-ERK signaling pathway, which is known to play important roles in carcinogenesis. qPCR verified increased expression of BRAF mRNA, and immunostaining and Western blot analysis demonstrated increased expression of p-ERK at the protein level suggested U19/EAF2 knockout activates this important pathway. These findings indicate that loss of EAF2 up-regulates transcription of RAS cascade genes including Grb2, PI3K, and BRAF, leading to elevated p-ERK levels, which may represent a major functional role of U19/EAF2 in the prostate. Furthermore, these observations suggest that U19/EAF2 is a key player in crosstalk between androgen receptor and the RAS-BRAF-ERK signaling pathway.

Many hypotheses have been proposed to try to explain cancer metastasis. However, they seem to be contradictory and have some limitations. Comparisons of primary tumors and matched metastases provide new insight into metastasis. The results show high concordances and minor differences at multiple scales from organic level to molecular level. The concordances reflect the commonality between primary cancer and metastasis, and also mean that metastatic cancer cells derived from primary cancer are quite conservative in distant sites. The differences reflect variation that cancer cells must acquire new traits to adapt to foreign milieu during the course of evolving into a new tumor in second organs. These comparisons also provided new information on understanding mechanism of vascular metastasis, organ-specific metastasis, and tumor dormancy. The collective results suggest a new hypothesis, biological resonance (bio-resonance) model. The hypothesis has two aspects. One is that primary cancer and matched metastasis have a common progenitor. The other is that both ancestors of primary cancer cells and metastatic cancer cells are under similar microenvironments and receive similar or same signals. When their interactions reach a status similar to primary cancer, metastasis will occur. Compared with previous hypotheses, the bio-resonance hypothesis seems to be more applicable for cancer metastasis to explain how, when and where metastasis occurs. Thus, it has important implications for individual prediction, prevention and treatment of cancer metastasis.

A series of overexpression studies have shown that lumican suppresses angiogenesis in tumors produced from pancreatic adenocarcinoma, fibrosarcoma, and melanoma tumor cells. Despite lumican's anti-angiogenic activity, a clear correlation of differential expression of lumican in various cancers and cancer malignancy has failed to emerge. Therefore, we hypothesized that either 1.) endogenously expressed lumican is not anti-angiogenic or alternatively that 2.) lumican exhibits angiostatic activity only in limited microenvironments. Previously, lumican was shown to suppress tumor growth and angiogenesis in subcutaneously injected PanO2 pancreatic adenocarcinoma cells. Therefore, to determine if endogenously expressed lumican is anti-angiogenic we subcutaneously injected PanO2 cells into wild-type and lumican knockout mice and compared tumor growth and vascular densities of the resulting tumors. We found that tumors grown in lumican knockout animals were larger and contained significantly elevated vascular densities compared to those grown in wild-type mice. Interestingly however lumican knockout animals did not exhibit enhanced angiogenesis in aortic ring assays, matrigel plugs, or healing wound biopsies raising the possibility that lumican suppresses angiogenesis only in tumor microenvironments. To test this possibility, we sought a tumor model wherein lumican did not exhibit anti-angiogenic activity. Utilizing the 4T1 breast cancer model, we found that lumican suppressed 4T1 tumor growth and lung metastasis, but not angiogenesis. In conclusion, these results show that the angiostatic activity of lumican is dependent on currently undefined microenvironmental cues and therefore helps to understand why differential expression of lumican does not consistently correlate with human tumor malignancy.

Reactive oxygen species (ROS) are implicated in many human diseases, including cancer. We have previously demonstrated that ROS increased the expression and activity of the chemokine receptor, CXCR4, which enhanced metastatic functions in prostate cancer cells. Studies have also revealed that CXCR4 and its ligand, SDF-1α, promoted ROS accumulation; however the source of ROS was not investigated. Recent evidence suggested that ROS accumulation in prostate cancer cell lines was contributed by the NADPH oxidase (NOX) family of enzymes. Herein, we sought to determine whether the CXCR4/SDF-1α signaling axis mediates ROS production through NOX in prostate cancer. We observed an increase in intracellular ROS generation in prostate cancer cells upon SDF-1α stimulation compared to untreated samples. Conversely, lower levels of ROS were detected in cells treated with AMD3100 (CXCR4 antagonist) or the ROS scavenger, N-acetyl-cysteine (NAC). Markedly reduced levels of ROS were observed in cells treated with apocynin (NOX inhibitor) compared to rotenone (mitochondrial complex I inhibitor)-treated cells. Specifically, we determined that NOX2 responded to, and was regulated by, the SDF-1α/CXCR4 signaling axis. Moreover, chemical inhibition of the ERK1/2 and PI3K pathways revealed that PI3K/AKT signaling participated in CXCR4-mediated NOX activity, and that these collective signaling events resulted in enhanced cell movement towards a chemoattractant. Finally, NOX2 may be a potential therapeutic target, as Oncomine microarray database analysis of normal prostate, benign prostatic hyperplasia (BPH) and prostatic intraepithelial neoplasia (PIN) tissue samples determined a correlation between NOX2 expression and prostate cancer. Taken together, these results suggest that CXCR4/SDF-1α-mediated ROS production through NOX2 enzymes may be an emerging concept by which chemokine signaling progresses tumorigenesis.