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The tumor microenvironment (TME) shows heterogeneity within a tumor. An important element of the TME is cancer-associated fibroblasts (CAF). In this issue of Cancer Research, Bouchard and colleagues investigate the heterogeneity of CAFs from spatially different zones of lung adenocarcinoma resection specimens. Multiomics analysis revealed changes in the O-glycoproteome, unique to CAFs from the tumor edge, an effect reinforced by contact with cancer cells. This O-glycoprotein signature offers unique targeting perspectives that reciprocally affect cancer cell epithelial-to-mesenchymal plasticity, a key mechanism of cancer progression. Deeper understanding of the cancer-stimulating and cancer-inhibiting role of CAF subtypes will facilitate the development of CAF-directed therapeutic approaches. See related article by Bouchard et al., p. 648., (©2022 American Association for Cancer Research.)

Tumor-derived secretory factors orchestrate splenic hematopoietic and stromal cells to fuel metastasis. The spleen acts as a reservoir site for hematopoietic stem and progenitor cells, which are rapidly exploited as myeloid-derived suppressor cells at the cost of tumor-reactive lymphoid cells. Splenic erythroid progenitor cells and mesenchymal stromal cells contribute directly and indirectly to both tumor immune escape and the metastatic cascade. Animal models provide valuable mechanistic insights, but their translation to a clinical setting highlights specific challenges and open issues. In this review, we envision the exploitation of the spleen as a source for novel biomarkers and therapeutic approaches., (©2020 American Association for Cancer Research.)

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival. Significance: These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. Cancer Res; 78(3); 659-70. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Increasing evidence supports the critical roles played by adipose tissue in breast cancer progression. Yet, the mediators and mechanisms are poorly understood. Here, we show that breast cancer-associated adipose tissue from freshly isolated tumors promotes F-actin remodeling, cellular scattering, invasiveness, and spheroid reorganization of cultured breast cancer cells. A combination of techniques, including transcriptomics, proteomics, and kinomics enabled us to identify paracrine secretion of oncostatin M (OSM) by cancer-associated adipose tissue. Specifically, OSM, expressed by CD45(+) leucocytes in the stromal vascular fraction, induced phosphorylation of STAT3 (pSTAT3-) Y705 and S727 in breast cancer cells and transcription of several STAT3-dependent genes, including S100 family members S100A7, S100A8, and S100A9. Autocrine activation of STAT3 in MCF-7 cells ectopically expressing OSM-induced cellular scattering and peritumoral neovascularization of orthotopic xenografts. Conversely, selective inhibition of OSM by neutralizing antibody and Jak family kinases by tofacitinib inhibited STAT3 signaling, peritumoral angiogenesis, and cellular scattering. Importantly, nuclear staining of pSTAT3-Y705 identified at the tumor invasion front in ductal breast carcinomas correlates with increased lymphovascular invasion. Our work reveals the potential of novel therapeutic strategies targeting the OSM and STAT3 axis in patients with breast cancer harboring nuclear pSTAT3-Y705., (©2014 American Association for Cancer Research.)

Cancer cells communicate with the environment through delivery of surface proteins, release of soluble factors (growth factors and cytokines), and sophisticated nanovehicles (exosomes) for establishment of invasive tumor growth. This communication occurs in part through constitutive exocytosis, regulated exocytosis, or release of intraluminal vesicles, and is modulated by small Rab GTPases, the master regulators of vesicle traffic. We studied Rab GTPases implicated in regulated exocytosis and showed a unique role for Rab27B in invasive tumor growth. Emerging evidence indicates that various exocytic routes are implemented by cancer cells to relay crucial information for fostering growth, migration, and matrix degradation.

Loss of NM23-H1 expression correlates with the degree of metastasis and with unfavorable clinical prognosis in several types of human carcinoma. However, the mechanistic basis for the metastasis suppressor function of NM23-H1 is obscure. We silenced NM23-H1 expression in human hepatoma and colon carcinoma cells and methodologically investigated effects on cell-cell adhesion, migration, invasion, and signaling linked to cancer progression. NM23-H1 silencing disrupted cell-cell adhesion mediated by E-cadherin, resulting in β-catenin nuclear translocation and T-cell factor/lymphoid-enhancing factor-1 transactivation. Further, NM23-H1 silencing promoted cellular scattering, motility, and extracellular matrix invasion by promoting invadopodia formation and upregulating several matrix metalloproteinases (MMP), including membrane type 1 MMP. In contrast, silencing the related NM23-H2 gene was ineffective at promoting invasion. NM23-H1 silencing activated proinvasive signaling pathways involving Rac1, mitogen-activated protein kinases, phosphatidylinositol 3-kinase (PI3K)/Akt, and src kinase. Conversely, NM23-H1 was dispensable for cancer cell proliferation in vitro and liver regeneration in NM23-M1 null mice, instead inducing cellular resistance to chemotherapeutic drugs in vitro. Analysis of NM23-H1 expression in clinical specimens revealed high expression in premalignant lesions (liver cirrhosis and colon adenoma) and the central body of primary liver or colon tumors, but downregulation at the invasive front of tumors. Our findings reveal that NM23-H1 is critical for control of cell-cell adhesion and cell migration at early stages of the invasive program in epithelial cancers, orchestrating a barrier against conversion of in situ carcinoma into invasive malignancy., (© 2010 AACR.)

Netrins and their receptors deleted in colon cancer (DCC), neogenin, UNC5, and integrins are involved in axon guidance, epithelial morphogenesis, vascular pattering, cancer cell survival, invasion, tumor angiogenesis, and metastasis. Here, we considered the possible contribution of the p53-related apoptosis mediators p63 and p73 in the mechanisms underlying the antagonism between netrin-1 and DCC at the cell death control. We have showed that ectopic expression and external addition of netrin-1 in HeLa and HEK-293 cells with inactive p53 lead to impaired cell viability and induction of apoptosis. These responses were associated with up-regulation of the proapoptotic protein TAp73alpha, decreased Bcl-2/Bax ratio, and caspase-3 cleavage, with no change in protein levels of the antiapoptotic NH(2)-terminal-truncated DeltaNp73alpha isoform, p73 adapter Yap-1 and p73 E3 ubiquitin ligase Itch, and p63, as well as the transcripts encoding p63, TAp73alpha, and DeltaNp73alpha. However, the proteasome inhibitor MG132 potentiated, while DCC counteracted, netrin-1-induced TAp73alpha. Consistently, netrin-1 expression correlated with stabilization of the TAp73alpha protein and lower levels of TAp73alpha ubiquitination that was conversely enhanced by DCC, in a netrin-dependent manner. Our data indicate that netrin-1 selectively up-regulates TAp73alpha by preventing its ubiquitination and degradation. Targeted repression of p73alpha by shRNA reversed TAp73alpha and the apoptosis induced by netrin-1, and exacerbated the growth of HeLa tumor xenografts. Apoptosis induced by cisplatin was markedly enhanced in netrin-1 or DCC-expressing cells. Collectively, our data reveal that the transcriptionally active TAp73alpha tumor suppressor is implicated in the apoptosis induced by netrin-1 in a p53-independent and DCC/ubiquitin-proteasome dependent manner.