The GcMAF Book

Chapter 17

Differentiation and Cancer Grading

Cancer cell “differentiation.” About cancer grading. Macrophages easily find undifferentiated cells because they display a higher degree of cell surface abnormality. GcMAF cure rates depend on the degree of cancer cell membrane abnormality, which corresponds to the grade of differentiation of malignant cells.

Under a microscope cancer cells don’t look like normal cells

In order to understand how cancers are graded, we need to have a short talk about cancer cell differentiation. Suppose you have a ripe banana. As it gradually goes bad, first a few minor brown spots appear on the surface. Then, as it approaches inedibility, it looks more and more rotten and it becomes progressively easier to make that determination. Cancer cells are like that. As the cancer progresses, the cells look (to macrophages) increasingly weirder and weirder, and as a consequence they become progressively easier to identify—and kill. Here’s how it works…

As they mature, normal cells “differentiate” into specialized cells. Cancer cells are different: they do not differentiate into mature specialized cells; they remain immature-looking. Cancer specialists therefore call them “undifferentiated.”

Well-differentiated (i.e., early stage) cancer cells look almost normal, but poorly-differentiated (more immature) cells do not look at all like normal cells. They look like more and more like cancer cells. Advanced cancers consist mostly of poorly differentiated (immature looking) or undifferentiated cells.

When macrophages are activated, they develop very large numbers of surface receptors that are programmed to spot cancer cell surface irregularities and then latch onto them. Since undifferentiated cancer cells have more surface irregularities, they are easier to locate. When the activated macrophages find them—well, by now you know the drill.

Cancer “grading”

The above facts are useful when trying to understand cancer grading. Degree of differentiation provides information about cancer aggressiveness and progression because the more normal (i.e., differentiated) a cancer cell looks, the lower its grade. The more abnormal or less well developed (i.e., undifferentiated) a cancer cell appears, the higher its grade. There are several grading systems, depending on the institution doing the grading and the tumor type. Here is a description of a typical three-tier grading system:

  • Grade 1: low grade or well differentiated cancer cells still look a lot like normal cells. These cancers are usually slow growing.
  • Grade 2: intermediate/moderate grade or moderately differentiated cancer cells do not look like normal cells. They are growing somewhat faster than normal cells.
  • Grade 3: high grade or poorly differentiated cancer cells do not look at all like normal cells. They are fast-growing or “aggressive.”

There is never any absolute certainty about how cancer cells will behave, but grade is a useful indicator. A low grade cancer will grow more slowly and be less likely to spread than a high grade one. Oncologists take cancer grade into consideration when pondering treatment decisions.


Poorly differentiated (immature) cancer cells are colored blue.

Why is differentiation important in terms of GcMAF?

The more undifferentiated a cancer cell is, the easier it is for GcMAF-activated macrophages to find it.

Like an advanced cancer cell, Waldo (of Where’s Waldo?) stands out in a huge crowd because he looks different. If Waldo were a cancer cell, activated macros would find him easily and he’d be toast in minutes; his little red and white striped shirt and funny glasses would be all that would be left behind.

The weirder the cancer cell looks, the easier the macros can recognize and destroy them. Undifferentiated (i.e., advanced or aggressive cancer cells) have more abnormalities on their cell surfaces, so—to activated macrophages—they look more “foreign” than earlier stage, well-differentiated cancer cells with fewer surface abnormalities. Therefore, undifferentiated cancer cells are more rapidly killed by activated macrophages because they “stand out” (like Waldo) in the crowd.

When macros are activated by GcMAF, their genome dramatically upregulates expression of the receptor proteins that identify cancer cells. More receptors translates into more “detectives” looking for Waldo, so he is lots easier to find.

Dr. Yamamoto showed that cancer cell surface abnormalities manifested a high correlation with GcMAF effectiveness. He also showed that macrophage activation caused dramatic increases in numbers of macrophage cell surface receptors that recognize a wide variety of cancer cell surface abnormalities.

in his 2008 paper on breast cancer Dr. Yamamoto describes these phenomena as follows: “Thus, the macrophages activated by GcMAF developed enormous variation of receptor that recognize a variety of microbial agents (e.g., bacteria and viruses) and abnormalities in malignant cell surfaces. This fundamental nature of macrophages to recognize cell surface abnormality (nonselfing nature) is universal to all types of cancers. In fact weekly administration of 100 ng GcMAF to cancer patients showed curative effects on a variety of cancers. Types of cancer so far tested are prostate, breast, colon, stomach, liver, lung (including mesothelioma), kidney, bladder, uterus, ovarian, head/neck, brain cancers, melanoma and fibrosarcoma. Efficacy of GcMAF therapy for cancers depends on the degree of cell membrane abnormality. Precision of measurement of Nagalase activity allowed us to determine the degree of cell surface abnormality by the curative rate during GcMAF therapy. Undifferentiated tumor cells are killed more efficiently than differentiated cells. In fact adenocarcinoma such as breast and prostate cancer cells are undifferentiated and killed rapidly by the activated macrophages whereas well-differentiated cancer cells such as squamous carcinoma cells are slowly killed by the activated macrophages. This curative rate appears to depend on both the amount of receptors for the particular antigen on macrophages and the amount of antigens on each cell.” (Int. J. Cancer: 122, 461–467 (2008). Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Nobuto Yamamoto, Hirofumi Suyama, Nobuyuki Yamamoto Naofumi Ushijima)

“Administration of 100 ng GcMAF per human results in the maximal level of macrophage activation which develop an enormous variation of receptors that recognize abnormality in malignant cell surface and kill cancerous cells. All malignant cells have abnormalities in their cell surface. A series of glycolipid, glycoprotein and mucin antigens have been identified and designated as tumor-associated antigen (TAA) on the cell surface of a wide variety of tumor cells. When human macrophages were treated in vitro with GcMAF (100 pg/ml) for 3 hr and a breast cancer cell line MCF-7 was added with effector/target ratio of 1.5, 60% and 86% of MCF-7 cells were killed in 4 hr and 18 hr incubation, respectively.” (Int. J. Cancer: 122, 461–467 (2008). Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Nobuto Yamamoto, Hirofumi Suyama, Nobuyuki Yamamoto Naofumi Ushijima)

Again in his 2008 prostate cancer paper Dr. Yamamoto comments on the connection between cell surface abnormalities, degree of differentiation, and effectiveness of GcMAF: “Efficacy of GcMAF therapy and curative rates of various cancers by GcMAF therapy depend on the degree of (cancer) cell membrane abnormality, which corresponds to the grade of differentiation of the malignant cells.” (Translational Oncology. 2008 July; 1(2): 65–72. Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF. Nobuto Yamamoto, Hirofumi Suyama, and Nobuyuki Yamamoto)

Copyright © 2010 Timothy J. Smith, M.D.