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IJMS
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Towards Personalized Treatment and Molecular Research on Colorectal Cancer
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Towards Personalized Treatment and Molecular Research on Colorectal Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 November 2024) | Viewed by 5555

Special Issue Editors

Prof. Dr. Emanuela Scarpi

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Guest Editor
Unit of Biostatistics and Clinical Trials, IRCCS-Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"- IRST-Srl, Via P. Maroncelli 40, 47014 Meldola, Italy
Interests: biostatistics; clinical trials; observational study; tumor epidemiology; oncology; palliative care; biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Paola Ulivi

E-Mail Website
Guest Editor
Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori” (IRST), via P. Maroncelli 40, 47014 Meldola, Italy
Interests: translational research; biomarkers; liquid biopsy; oncology
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandro Passardi

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Guest Editor
Department of Medical Oncology, IRCCS-Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"- IRST-Srl, Via P. Maroncelli 40, 47014 Meldola, Italy
Interests: translational research; angiogenesis; colorectal cancer; pancreatic cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females. The genome of colon cancer cells is altered at several sites as a result of point mutations or changes in chromosome integrity. The mutation-associated changes affect oncogenes, tumor suppressor genes, and several metastasis-related genes. Other factors including epigenetic alterations as well as the deregulation of miRNA-mediated control of mRNA functions, contribute to the incidence of cancer and metastasis.

Translational research has led to significant benefits in CRC screening and patient management, and precision medicine is fast becoming the aim of scientific research. Individualized treatment for CRC in both adjuvant and metastatic settings is increasingly emphasized. The introduction of molecular-targeted agents with anti-epidermal growth factor receptor (EGFR) or anti-angiogenic mechanisms of action has significantly improved patient outcome, but predictive markers of efficacy, especially for angiogenesis inhibition, are still lacking. Furthermore immunotherapy has recently been implemented into clinical practice.

A new approach to biomarker detection is the use of liquid biopsy. Free circulating tumor DNA (fctDNA) can be monitored quantitatively and qualitatively for diagnostic, prognostic, or predictive purposes. Liquid biopsy has the potential to replace tumor tissue analysis in clinical practice and could be used to monitor the extent of tumor burden and to detect tumor heterogeneity and molecular resistance to therapy.

Prof. Dr. Emanuela Scarpi
Dr. Paola Ulivi
Dr. Alessandro Passardi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • adenoma-carcinoma sequence
  • predictive biomarkers of response and toxicity in the adjuvant and metastatic settings
  • genetic and epigenetic marker
  • immunotherapy
  • prognostic biomarkers
  • angiogenesis
  • EGFR pathways
  • tumor biopsies
  • circulating tumor cells
  • tumor heterogeneity
  • early diagnosis
  • screening
  • liquid biopsy
  • molecular pathology
  • tumor biology

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (3 papers)

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Research

11 pages, 754 KiB  
Article
Multigene Panel Next-Generation Sequencing Techniques in the Management of Patients with Metastatic Colorectal Carcinoma: The Way Forward for Personalized Treatment? A Single-Center Experience
by Laura Matteucci, Francesco Giulio Sullo, Chiara Gallio, Luca Esposito, Margherita Muratore, Ilario Giovanni Rapposelli, Daniele Calistri, Elisabetta Petracci, Claudia Rengucci, Laura Capelli, Elisa Chiadini, Paola Ulivi, Alessandro Passardi and Alessandro Bittoni
Int. J. Mol. Sci. 2024, 25(20), 11071; https://doi.org/10.3390/ijms252011071 - 15 Oct 2024
Viewed by 984
Abstract
The efficacy and cost-effectiveness of Multigene Panel Next-Generation Sequencing (NGS) in directing patients towards genomically matched therapies remain uncertain. This study investigated metastatic colorectal cancer (mCRC) patients who underwent NGS analysis on formalin-fixed paraffin-embedded tumor samples. Data from 179 patients were analyzed, revealing [...] Read more.
The efficacy and cost-effectiveness of Multigene Panel Next-Generation Sequencing (NGS) in directing patients towards genomically matched therapies remain uncertain. This study investigated metastatic colorectal cancer (mCRC) patients who underwent NGS analysis on formalin-fixed paraffin-embedded tumor samples. Data from 179 patients were analyzed, revealing no mutations in 39 patients (21.8%), one mutation in 83 patients (46.4%), and two or more mutations in 57 patients (31.8%). KRAS mutations were found in 87 patients (48.6%), including KRAS G12C mutations in 5 patients (2.8%), PIK3CA mutations in 40 patients (22.4%), and BRAF mutations in 26 patients (14.5%). Less common mutations were identified: ERBB2 in five patients (2.8%) and SMO in four patients (2.2%). Additionally, MAP2K1, CTNNB1, and MYC were mutated in three patients (2.4%). Two mutations (1.1%) were observed in ERBB3, RAF1, MTOR, JAK1, and FGFR2. No significant survival differences were observed based on number of mutations. In total, 40% of patients had druggable molecular alterations, but only 1.1% received genomically guided treatment, suggesting limited application in standard practice. Despite this, expanded gene panel testing can identify actionable mutations, aiding personalized treatment strategies in metastatic CRC, although current eligibility for biomarker-guided trials remains limited. Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Colorectal Cancer)
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Figure 1

Figure 1
<p>Pie chart of the number of alterations per patient.</p> Full article ">Figure 2
<p>Kaplan–Meier curves for progression-free survival (<b>left</b>) and overall survival (<b>right</b>) based on the mutational status of <span class="html-italic">BRAF</span> gene.</p> Full article ">
17 pages, 2896 KiB  
Article
Pexidartinib and Immune Checkpoint Inhibitors Combine to Activate Tumor Immunity in a Murine Colorectal Cancer Model by Depleting M2 Macrophages Differentiated by Cancer-Associated Fibroblasts
by Daisuke Shimizu, Ryo Yuge, Yuki Kitadai, Misa Ariyoshi, Ryo Miyamoto, Yuichi Hiyama, Hidehiko Takigawa, Yuji Urabe and Shiro Oka
Int. J. Mol. Sci. 2024, 25(13), 7001; https://doi.org/10.3390/ijms25137001 - 26 Jun 2024
Cited by 4 | Viewed by 2006
Abstract
Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both [...] Read more.
Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both in vitro and in vivo. When co-cultured with monocytes, CAFs attracted monocytes and induced their differentiation into M2 macrophages. Immunohistology of surgically resected human CRC specimens and orthotopically transplanted mouse tumors revealed a correlation between numbers of CAFs and numbers of M2 macrophages. In a mouse model of CRC orthotopic transplantation, treatment with an inhibitor of the colony-stimulating factor-1 receptor (PLX3397) depleted M2 macrophages and increased CD8-positive T cells infiltrating the tumor nest. While this treatment had a minor effect on tumor growth, combining PLX3397 with anti-PD-1 antibody significantly reduced tumor growth. RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC. Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Colorectal Cancer)
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Figure 1

Figure 1
<p>In culture, cancer-associated fibroblasts (CAFs) derived from colorectal cancer (CRC) cells attract J774.1 cells (transfected with a construct expressing fluorescent luciferase) to the CAF periphery and induce their differentiation into M2 macrophages. (<b>a</b>) J774.1 cells in monoculture incubated for 48 h. (<b>b</b>) J774.1 cells in monoculture incubated with IL-4 for 48 h. (<b>c</b>) J774.1 cells and CAFs co-cultured for 48 h. (<b>d</b>) J774.1 cells co-cultured with BALB/c MSCs for 48 h. (<b>e</b>) J774.1 cells co-cultured with C57BL/6 MSCs for 48 h. (<b>f</b>–<b>i</b>) Expression measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in J774.1 cells cultured alone, cultured with IL-4, and co-cultured with CAFs, BALB/c MSCs, and C57BL/6 MSCs for 48 h, of (<b>f</b>) the M2 marker CD206; (<b>g</b>) the M1 marker iNos; (<b>h</b>) the M1 marker IL-1; and (<b>i</b>) the M1 marker IL-6. Data are presented as means ± s.d.</p> Full article ">Figure 2
<p>Abundance of cancer-associated fibroblasts (CAFs) correlates with abundance of M2 macrophages in human colorectal cancer (CRC). (<b>a</b>) Immunofluorescence staining for αSMA and CD163. (<b>b</b>) Scatterplot from 73 samples of αSMA-positive areas and CD163-positive cell counts. R, correlation coefficient.</p> Full article ">Figure 3
<p>Cancer-associated fibroblasts (CAFs) increase M2 macrophage abundance in an orthotopic transplant mouse model of colorectal cancer (CRC). (<b>a</b>) Fluorescence immunostaining for αSMA and CD163 in transplanted tumors in a CRC orthotopic mouse model with MC38-only control (top row) and MC38 and CAFs co-transplanted (bottom row) into C57BL/6 mice. (<b>b</b>) αSMA-positive areas. (<b>c</b>) Numbers of CD163-positive cells. Data are presented as means ± s.d.; * <span class="html-italic">p</span> &lt; 0.01 by unpaired two-sided Student’s <span class="html-italic">t</span>-test.</p> Full article ">Figure 4
<p>M2 macrophages inhibit tumor immunity by blocking tumor infiltration of CD8-positive T cells. (<b>a</b>) CD8-positive T cells in contact with M2 macrophages in tumor stromal-rich areas observed by fluorescence immunostaining for CD163 and CD8 in a colorectal cancer (CRC) orthotopic mouse model using co-transplantation of MC38 and cancer-associated fibroblasts (CAFs). (<b>b</b>) Tumor volumes 35 days after treatment in control, anti-PD-1 antibody monotherapy, PLX3397 monotherapy, and combination therapy groups, using the orthotopic transplant mouse model with co-transplantation. (<b>c</b>) Immunostaining for CD8 and Ki67. Red arrows indicate CD8-positive cells accumulating in the stroma around the tumor nest. (<b>d</b>) Ki67 labeling indices. Data are presented as means ± s.d.; * <span class="html-italic">p</span> &lt; 0.01; ** <span class="html-italic">p</span> &lt; 0.05; n.s., not significant using an unpaired, two-sided Student’s <span class="html-italic">t</span>-test.</p> Full article ">Figure 5
<p>M2 macrophages induce an immunosuppressive orientation of the tumor microenvironment in an orthotopic mouse model of colorectal cancer (CRC). (<b>a</b>) Fluorescence immunostaining for αSMA, CD163, CD8, and CD4. (<b>b</b>) αSMA-positive areas and numbers of CD163-, CD8-, and CD4-positive cells in transplanted tumors in therapeutic experiments. Data are presented as means ± s.d.; * <span class="html-italic">p</span> &lt; 0.01; n.s., not significant using an unpaired, two-sided Student’s <span class="html-italic">t</span>-test.</p> Full article ">Figure 5 Cont.
<p>M2 macrophages induce an immunosuppressive orientation of the tumor microenvironment in an orthotopic mouse model of colorectal cancer (CRC). (<b>a</b>) Fluorescence immunostaining for αSMA, CD163, CD8, and CD4. (<b>b</b>) αSMA-positive areas and numbers of CD163-, CD8-, and CD4-positive cells in transplanted tumors in therapeutic experiments. Data are presented as means ± s.d.; * <span class="html-italic">p</span> &lt; 0.01; n.s., not significant using an unpaired, two-sided Student’s <span class="html-italic">t</span>-test.</p> Full article ">Figure 6
<p>Gene expression analysis confirming immune pathway activation in transplanted tumors upon combined PLX3397 and anti-PD-1 antibody treatment. (<b>a</b>) Gene Ontology (GO) cellular component enrichment bubble chart. (<b>b</b>) KEGG pathway enrichment bubble chart.</p> Full article ">
15 pages, 7402 KiB  
Article
Simultaneous Expression of CD70 and POSTN in Cancer-Associated Fibroblasts Predicts Worse Survival of Colorectal Cancer Patients
by Masayuki Komura, Chengbo Wang, Sunao Ito, Shunsuke Kato, Akane Ueki, Masahide Ebi, Naotaka Ogasawara, Toyonori Tsuzuki, Kenji Kasai, Kunio Kasugai, Shuji Takiguchi, Satoru Takahashi and Shingo Inaguma
Int. J. Mol. Sci. 2024, 25(5), 2537; https://doi.org/10.3390/ijms25052537 - 22 Feb 2024
Cited by 3 | Viewed by 1980
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide, with high morbidity and mortality rates. The evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) that modulate cancer cell proliferation, invasion, metastasis, and tumor immunity, including in CRC, has been [...] Read more.
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide, with high morbidity and mortality rates. The evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) that modulate cancer cell proliferation, invasion, metastasis, and tumor immunity, including in CRC, has been attracting attention. The present study examined the expression status of CD70 and POSTN in CRC and analyzed their association with clinicopathological features and clinical outcomes. In the present study, in total 15% (40/269) and 44% (119/269) of cases exhibited CD70 and POSTN expression on CAFs, respectively. Co-expression of CD70 and POSTN was detected in 8% (21/269) of patients. Fluorescent immunohistochemistry identified the co-expression of CD70 and POSTN with FAP and PDPN, respectively. ACTA2 was not co-expressed with CD70 or POSTN in CRC CAFs. CRC with CD70+/POSTN+ status in CAFs was significantly associated with distant organ metastasis (p = 0.0020) or incomplete resection status (p = 0.0011). CD70+/POSTN+ status tended to associate with advanced pT stage (p = 0.032) or peritoneal metastasis (p = 0.0059). Multivariate Cox hazards regression analysis identified CD70+/POSTN+ status in CAFs [hazard ratio (HR) = 3.78] as a potential independent risk factor. In vitro experiments revealed the activated phenotypes of colonic fibroblasts induced by CD70 and POSTN, while migration and invasion assays identified enhanced migration and invasion of CRC cells co-cultured with CD70- and POSTN-expressing colonic fibroblasts. On the basis of our observations, CD70 and POSTN immunohistochemistry can be used in the prognostication of CRC patients. CRC CAFs may be a promising target in the treatment of CRC patients. Full article
(This article belongs to the Special Issue Towards Personalized Treatment and Molecular Research on Colorectal Cancer)
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Figure 1

Figure 1
<p>Representative images of CD70 and POSTN immunostaining in CRC. In non-neoplastic colonic mucosa, CD70 was weakly expressed on the immune cells. POSTN was expressed on the stromal cells. Both CD70 and POSTN were expressed on CRC CAFs. Bar, 200 μm.</p> Full article ">Figure 2
<p>Representative images of fluorescent immunostaining in CRC. (<b>a</b>) Fluorescent immunohistochemistry identified co-expression of CD70 and POSTN on CRC CAFs. (<b>b</b>) CD70 and FAP were co-expressed in some of the CRC CAFs. (<b>c</b>) POSTN was co-expressed with PDPN in some. (<b>d</b>,<b>e</b>) ACTA2 was not co-expressed with CD70 (<b>d</b>) or POSTN (<b>e</b>) in CRC CAFs. T, tumor. Bar, 50 μm.</p> Full article ">Figure 3
<p>Cellular proliferation marker expression classified according to CD70 and POSTN expression. (<b>a</b>–<b>d</b>) CD70−/POSTN+ CRC showed significantly lower expression of PHH3 (<b>a</b>), CCDN (<b>b</b>), and GMNN (<b>c</b>). No significant association was detected between CD70 and POSTN expression status and Ki-67 (<b>d</b>). *, <span class="html-italic">p</span> &lt; 0.05; **, <span class="html-italic">p</span> &lt; 0.01. The circles indicate outliers.</p> Full article ">Figure 4
<p>CAF CD70 and POSTN expression was significantly associated with immune cell infiltration. CD70 and POSTN were significantly associated with CD8- (<b>a</b>) and CD68-positive immune cells (<b>b</b>) in CRC. *, <span class="html-italic">p</span> &lt; 0.05; **, <span class="html-italic">p</span> &lt; 0.01. The circles indicate outliers.</p> Full article ">Figure 5
<p>Overall survival of CRC patients classified according to CD70 and POSTN expression on CAFs. Patients with CRC exhibiting stromal CD70 and POSTN expression showed the worst clinical outcomes. The post hoc test identified significant differences as follows: CD70+/POSTN+ vs. CD70−/POSTN− (<span class="html-italic">p</span> = 0.00036); CD70+/POSTN+ vs. CD70−/POSTN+ (<span class="html-italic">p</span> = 0.028). Survival at 5-year was indicated by dashed line.</p> Full article ">Figure 6
<p>Effects of CD70 and POSTN on colonic fibroblasts. (<b>a</b>) Exogenous expression of CD70 and/or POSTN in human colonic fibroblast CCD-18Co upregulated ACTA2, PDPN, MMP2, and STAT3 expression, whereas FAP was downregulated. Additive effects of CD70 and POSTN were observed for MMP2, STAT3, and phosphorylated STAT3. Note that POSTN secreted into the culture medium was analyzed by immune blots. (<b>b</b>) Cellular proliferation of CCD-18Co was significantly upregulated by CD70 and POSTN. Assays were performed in triplicate. Data are presented as the mean ± SD. **, <span class="html-italic">p</span> &lt; 0.01.</p> Full article ">Figure 7
<p>Co-culture migration and invasion assays. (<b>a</b>) The migration of EGFP-tagged HCT-116 cells was significantly enhanced when they were co-cultured with CCD-18Co<sup>LacZ/CD70</sup>, CCD-18Co<sup>POSTN/LacZ</sup>, and CCD-18Co<sup>POSTN/CD70</sup>. Assays were performed in triplicate. Data are presented as the mean ± SD. **, <span class="html-italic">p</span> &lt; 0.01. (<b>b</b>) EGFP-labeled HCT-116 cells co-cultured with CCD-18Co<sup>POSTN/CD70</sup> uniquely showed significantly more enhanced invasiveness than CCD-18Co<sup>LacZ/LacZ</sup>. Assays were performed in triplicate. Data are presented as the mean ± SD. *, <span class="html-italic">p</span> &lt; 0.05. (<b>c</b>) Representative images of the results for migration assays. Bar, 200 µm.</p> Full article ">
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