The use of various transgenic mouse models and analysis of human tumour biopsies has shown that bone marrow-derived myeloid cells, such as macrophages, neutrophils, eosinophils, mast cells and dendritic cells, have an important role in regulating the formation and maintenance of blood vessels in tumours. In this Review the evidence for each of these cell types driving tumour angiogenesis is outlined, along with the mechanisms regulating their recruitment and activation by the tumour microenvironment. We also discuss the therapeutic implications of recent findings that specific myeloid cell populations modulate the responses of tumours to agents such as chemotherapy and some anti-angiogenic therapies.

The role of myeloid cells in the promotion of tumour angiogenesis

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The identification and characterization of regulatory T (T(Reg)) cells that can control immune responsiveness to alloantigens have opened up exciting opportunities for new therapies in transplantation. After exposure to alloantigens in vivo, alloantigen-specific immunoregulatory activity is enriched in a population of CD4+ T cells that express high levels of CD25. In vivo, common mechanisms seem to underpin the activity of CD4+CD25+ T(Reg) cells in both naive and manipulated hosts. However, the origin, allorecognition properties and molecular basis for the suppressive activity of CD4+CD25+ T(Reg) cells, as well as their relationship to other populations of regulatory cells that exist after transplantation, remain a matter of debate..

Regulatory T cells in transplantation tolerance.

Background Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive factors (factors predicting response to therapy) in colorectal carcinoma was evaluated. A multidisciplinary group of clinical (including the disciplines of medical oncology, surgical oncology, and radiation oncology), pathologic, and statistical experts in colorectal cancer reviewed all relevant medical literature and stratified the reported prognostic factors into categories that reflected the strength of the published evidence demonstrating their prognostic value. Accordingly, the following categories of prognostic factors were defined. Category I includes factors definitively proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management. Category IIA includes factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value for outcome and/or predictive value for therapy that is of sufficient import to be included in the pathology report but that remains to be validated in statistically robust studies. Category IIB includes factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA. Category III includes factors not yet sufficiently studied to determine their prognostic value. Category IV includes factors well studied and shown to have no prognostic significance. Materials and methods The medical literature was critically reviewed, and the analysis revealed specific points of variability in approach that prevented direct comparisons among published studies and compromised the quality of the collective data. Categories of variability recognized included the following: (1) methods of analysis, (2) interpretation of findings, (3) reporting of data, and (4) statistical evaluation. Additional points of variability within these categories were defined from the collective experience of the group. Reasons for the assignment of an individual prognostic factor to category I, II, III, or IV (categories defined by the level of scientific validation) were outlined with reference to the specific types of variability associated with the supportive data. For each factor and category of variability related to that factor, detailed recommendations for improvement were made. The recommendations were based on the following aims: (1) to increase the uniformity and completeness of pathologic evaluation of tumor specimens, (2) to enhance the quality of the data needed for definitive evaluation of the prognostic value of individual prognostic factors, and (3) ultimately, to improve patient care. Results and conclusions Factors that were determined to merit inclusion in category I were as follows: the local extent of tumor assessed pathologically (the pT category of the TNM staging system of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer [AJCC/UICC]); regional lymph node metastasis (the pN category of the TNM staging system); blood or lymphatic vessel invasion; residual tumor following surgery with curative intent (the R classification of the AJCC/UICC staging system), especially as it relates to positive surgical margins; and preoperative elevation of carcinoembryonic antigen elevation (a factor established by laboratory medicine methods rather than anatomic pathology). Factors in category IIA included the following: tumor grade, radial margin status (for resection specimens with nonperitonealized surfaces), and residual tumor in the resection specimen following neoadjuvant therapy (the ypTNM category of the TNM staging system of the AJCC/UICC). (ABSTRACT TRUNCATED)

Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999.

Maintenance of epithelial tissues needs the stroma. When the epithelium changes, the stroma inevitably follows. In cancer, changes in the stroma drive invasion and metastasis, the hallmarks of malignancy. Stromal changes at the invasion front include the appearance of myofibroblasts, cells sharing characteristics with fibroblasts and smooth muscle cells. The main precursors of myofibroblasts are fibroblasts. The transdifferentiation of fibroblasts into myofibroblasts is modulated by cancer cell-derived cytokines, such as transforming growth factor-beta (TGF-beta). TGF-beta causes cancer progression through paracrine and autocrine effects. Paracrine effects of TGF-beta implicate stimulation of angiogenesis, escape from immunosurveillance and recruitment of myofibroblasts. Autocrine effects of TGF-beta in cancer cells with a functional TGF-beta receptor complex may be caused by a convergence between TGF-beta signalling and beta-catenin or activating Ras mutations. Experimental and clinical observations indicate that myofibroblasts produce pro-invasive signals. Such signals may also be implicated in cancer pain. N-Cadherin and its soluble form act as invasion-promoters. N-Cadherin is expressed in invasive cancer cells and in host cells such as myofibroblasts, neurons, smooth muscle cells, and endothelial cells. N-Cadherin-dependent heterotypic contacts may promote matrix invasion, perineural invasion, muscular invasion, and transendothelial migration; the extracellular, the juxtamembrane and the beta-catenin binding domain of N-cadherin are implicated in positive invasion signalling pathways. A better understanding of stromal contributions to cancer progression will likely increase our awareness of the importance of the combinatorial signals that support and promote growth, dedifferentiation, invasion, and ectopic survival and eventually result in the identification of new therapeutics targeting the stroma.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.1398

Role of tissue stroma in cancer cell invasion.

The relation between tumor-associated macrophage (TAM) density and the density of microvessels was investigated in specimens from 113 patients with pulmonary adenocarcinoma, as was the influence of TAM density on prognosis. The rank correlation test revealed a significant relation between TAM density and microvessel density (y = 14.418 + 0.863x, r = 0.454, p > 0.0001). A significant difference in patient survival rate was detected between tumors with a TAM density defined as high and those with a TAM density defined as low (p < 0.01). Multivariate analysis also showed that TAM density was significantly related to survival (p < 0.05). These data indicate that TAM infiltration may contribute to tumor angiogenesis, and that TAM density is a useful prognostic marker in pulmonary adenocarcinoma.

Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: association with angiogenesis and poor prognosis.

Background. Many studies on postoperative carcinoembryonic antigen (CEA) and/or carbohydrate antigen (CA)19-9 monitoring after operation for gastric cancer have been reported, but most have been retrospective.

/pdf/the-usefulness-of-cea-and-or-ca19-9-in-monitoring-for-4qyso2bzk9.pdf

The usefulness of CEA and/or CA19-9 in monitoring for recurrence in gastric cancer patients: a prospective clinical study

In order to discover the incidence of recurrence and prognosis of patients with anastomotic leakage after colorectal surgery, 980 colorectal cancer patients who underwent anastomosis at Keio University Hospital between 1970 and 1990 were examined. Thirty-three patients (leakage group) out of the 980 exhibited anastomotic leakage. The incidence of local recurrence in the leakage group was significantly higher than in the no leakage group (P < 0.01). The disease-free survival rate of the leakage group was significantly lower than that of the no leakage group in Dukes' A, B patients (P < 0.01), but was not so in Dukes' C, D patients. These results suggested that anastomotic leakage after colorectal cancer surgery might enhance the incidence of local recurrence and make the prognosis poor.

Anastomotic leakage after colorectal cancer surgery: a risk factor for recurrence and poor prognosis.

Purpose This study was designed to examine trends of colorectal cancer in relation to age, gender, site, and survival during the past 20 years. Methods The multi-institutional registry of the Japanese Society for Cancer of the Colon and Rectum offered 87,695 surgical cases with invasive adenocarcinoma during 1978 to 1997 for analysis. We calculated survival rates and used the Cox's proportional hazard model for cases during 1978 to 1994. Results The number of cases showed a 2.5-fold increase with consistent male predominance confined to the distal colon and the rectum. Colon cancer in the last five-year period was more likely right-sided for females (odds ratio, 1.26; 95 percent confidence interval, 1.16-1.38) and males (odds ratio, 1.16; 95 percent confidence interval, 1.06-1.25) compared with the first period. Cancers in younger patients were more likely at Stage III to IV in the late 1990s if the cancers were in the distal colon, the rectum (for both genders), or the proximal colon (for females). Survival was improved except for cases with proximal colon cancer of Stage IV. In the multivariate analysis, hazard ratios for death in the postoperative five years were 0.77, 0.59, and 0.66 for proximal colon, distal colon, and rectal cancers, respectively, in the last period as compared with those in the first period [corrected]. Reduced hazard ratio for females was the largest for proximal colon cancer with Stage I to II. Conclusion Although surgical outcome was largely improved, delayed presentation or diagnosis in younger patients remained a problem. Preferential localization in the proximal colon and survival benefit for females should be investigated.

Changes in colorectal cancer during a 20-year period: an extended report from the multi-institutional registry of large bowel cancer, Japan.

PURPOSE: Diverticulosis of the right colon has been increasing in the Far East; however, a considerable proportion of these patients includes cases of solitary right-sided diverticular disease. This study aimed to determine whether the incidence of such solitary diverticula (defined as 1 or 2 diverticula in this study) and multiple (3 or more) diverticula of the right colon is increasing in Japan. METHODS: A total of 13,947 consecutive barium enema examinations, performed in the period from 1982 to 1997, were reviewed. Changes in the frequency (detection rate) and number of diverticula across time and with aging of three types of diverticula, right-sided, left-sided, and bilateral, were investigated, with special interest in those patients with one or two diverticula of the right colon. RESULTS: Right-sided and bilateral diverticula have increased in frequency across time; however, left-sided diverticula have not. Patients with one or two diverticula in the right colon of right-sided disease, unexpectedly, have increased across time in both genders, and patients with three or more diverticula in the right colon of right-sided disease have shown an increase in males. The number of diverticula of the right colon showed no increase across time or with aging. CONCLUSIONS: Diverticulosis of the right colon, both solitary and multiple, has been increasing steadily in Japan; therefore, diverticulitis and bleeding diverticula of the right colon may continue to increase. Diverticula of the right colon might be an acquired disease and self-limiting in development, because the frequency did not increase substantially in the elderly and because the number changed little across time and with aging.

Susumu Kodaira

Papers

Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: association with angiogenesis and poor prognosis.

The usefulness of CEA and/or CA19-9 in monitoring for recurrence in gastric cancer patients: a prospective clinical study

Anastomotic leakage after colorectal cancer surgery: a risk factor for recurrence and poor prognosis.

Changes in colorectal cancer during a 20-year period: an extended report from the multi-institutional registry of large bowel cancer, Japan.

Recent trends in diverticulosis of the right colon in Japan: retrospective review in a regional hospital.